Tetralin and indane derivatives and uses thereof

ABSTRACT

Compounds of the formula I: 
     
       
         
         
             
             
         
       
         
         or pharmaceutically acceptable salts thereof, 
         wherein m, p, q, Ar, R 1  and R 2  are as defined herein. Also provided are methods for preparing, compositions comprising, and methods for using compounds of formula I.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of priority of U.S. ProvisionalPatent Application Ser. No. 60/638,030 filed Dec. 21, 2004, thedisclosure of which is incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

This invention relates to substituted indane and tetralin compounds, andassociated compositions, methods for use as therapeutic agents, andmethods of preparation thereof.

BACKGROUND OF THE INVENTION

The actions of 5-hydroxytryptamine (5-HT) as a major modulatoryneurotransmitter in the brain are mediated through a number of receptorfamilies termed 5-HT1, 5-HT2, 5-HT3, 5-HT4, 5-HT5, 5-HT6, and 5-HT7.Based on a high level of 5-HT6 receptor mRNA in the brain, it has beenstated that the 5-HT6 receptor may play a role in the pathology andtreatment of central nerve system disorders. In particular,5-HT2-selective and 5-HT6 selective ligands have been identified aspotentially useful in the treatment of certain CNS disorders such asParkinson's disease, Huntington's disease, anxiety, depression, manicdepression, psychoses, epilepsy, obsessive compulsive disorders, mooddisorders, migraine, Alzheimer's disease (enhancement of cognitivememory), sleep disorders, feeding disorders such as anorexia, bulimiaand obesity, panic attacks, akathisia, attention deficit hyperactivitydisorder (ADHD), attention deficit disorder (ADD), withdrawal from drugabuse such as cocaine, ethanol, nicotine and benzodiazepines,schizophrenia, and also disorders associated with spinal trauma and/orhead injury such as hydrocephalus. Such compounds are also expected tobe of use in the treatment of certain gastrointestinal (GI) disorderssuch as functional bowel disorder. See for example, B. L. Roth et al.,J. Pharmacol. Exp. Ther., 1994, 268, pages 1403-14120, D. R. Sibley etal., Mol. Pharmacol., 1993, 43, 320-327, A. J. Sleight et al.,Neurotransmission, 1995, 11, 1-5, and A. J. Sleight et al., Serotonin IDResearch Alert, 1997, 2(3), 115-8.

While some 5-HT6 and 5-HT2A modulators have been disclosed, therecontinues to be a need for compounds that are useful for modulating the5-HT6 receptor, the 5-HT2A receptor, or both.

SUMMARY

The invention provides compounds of the formula I:

-   or a pharmaceutically acceptable salt thereof,-   wherein:

m is from 0 to 3;

p is from 1 to 3;

q is 0, 1 or 2;

Ar is optionally substituted aryl or optionally substituted heteroaryl;

is an optional bond;

each R¹ is independently halo, alkyl, haloalkyl, alkoxy, hydroxy,heteroalkyl, cyano, —S(O)_(t)—R^(a), —C(═O)—NR^(b)R^(c),—SO₂—NR^(b)R^(c), —N(R^(d))—C(═O)—R^(e), or —C(═O)—R^(e), where t isfrom 0 to 2, R^(a), R^(b), R^(c), R^(d) and R^(e) each independently ishydrogen or alkyl, and R^(f) is hydrogen, alkyl, alkoxy or hydroxy;

R² is

n is from 1 to 3;

R³ and R⁴ each independently is hydrogen or alkyl, or R³ and R⁴ togethermay form ═O or ═NR^(f) wherein R^(f) is hydrogen or alkyl; and

one of R⁵ and R⁶ is hydrogen or alkyl and the other is: hydrogen; alkyl;amidinyl; aminocarbonyl; alkylcarbonyl; alkoxycarbonyl;aminocarbonylalkyl; aminoalkylcarbonyl; alkoxycarbonylalkyl;imidazolonyl; imidazolylcarbonyl; pyrrolylcarbonyl;pyrrolidinylcarbonyl; N-cyanoamidinyl; alkylsulfonyl;hydroxyalkylcarbonyl; aminosulfonyl; hydroxyalkyl; alkoxalkyl;alkylsulfonylalkyl; or optionally substituted heteroaryl; or

R⁵ and R⁶ together with the nitrogen to which they are attached may forman amidinyl group, a urea group, a guanidinyl group or a five- orsix-membered heteroaryl or heterocyclyl ring that is optionallysubstituted and which optionally includes an additional heteroatomselected from O, N and S; or

one of R⁵ and R⁶ and one of R³ and R⁴ together with the atoms to whichthey are attached may form a five- or six-membered ring that optionallyincludes an additional heteroatom selected from O, N and S.

The invention also provides methods for preparing, methods of using, andpharmaceutical compositions comprising the aforementioned compounds.

DETAILED DESCRIPTION OF THE INVENTION

The invention provides substituted quinolinone compounds, associatedcompositions, methods for use as therapeutic agents, and methods ofpreparation thereof. In specific embodiments the invention providespiperazinyl-substituted quinolinone compounds and associatedpharmaceutical compositions, and methods for using the same in thetreatment of central nervous system (CNS) diseases and gastrointestinaltract disorders.

All publications cited in this disclosure are incorporated herein byreference in their entirety.

Definitions

Unless otherwise stated, the following terms used, in this Application,including the specification and claims, have the definitions givenbelow. It must be noted that, as used in the specification and theappended claims, the singular forms “a”, “an,” and “the” include pluralreferents unless the context clearly dictates otherwise.

“Agonist” refers to a compound that enhances the activity of anothercompound or receptor site.

“Antagonist” refers to a compound that diminishes or prevents the actionof another compound or receptor site.

“Alkyl” means the monovalent linear or branched saturated hydrocarbonmoiety, consisting solely of carbon and hydrogen atoms, having from oneto twelve carbon atoms. “Lower alkyl” refers to an alkyl group of one tosix carbon atoms (i.e., “C₁-C₆alkyl”). Examples of alkyl groups include,but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl,sec-butyl, tert-butyl, pentyl, n-hexyl, octyl, dodecyl, and the like.

“Alkylene” means a linear saturated divalent hydrocarbon radical of oneto six carbon atoms or a branched saturated divalent hydrocarbon radicalof three to six carbon atoms, e.g., methylene, ethylene,2,2-dimethylethylene, propylene, 2-methylpropylene, butylene, pentylene,and the like.

“Alkenylene” means a linear unsaturated divalent hydrocarbon radical oftwo to six carbon atoms or a branched saturated divalent hydrocarbonradical of three to six carbon atoms, e.g., ethenylene (—CH═CH—),2,2-dimethylethenylene, propenylene, 2-methylpropenylene, butenylene,pentenylene, and the like.

“Alkylcarbonyl means a group of the formula —C(O)—R wherein R is alkylas defined herein.

“Alkylcarbonylaminoalkyl” means a group of the formula —R—NR′—R″ whereinR is alkylene, R′ is hydrogen or alkyl, and R″ is alkylcarbonyl asdefined herein.

“Alkylsulfonyl means a group —SO₂—R wherein R is alkyl as definedherein.

“Alkylsulfonylalkyl means a group —R—SO₂—R′ wherein R′ is alkyl and R isalkylene as defined herein.

“Alkylsulfonylalkylaminoalkyl” means a group of the formula —R—NR′—R″wherein R is alkylene, R′ is hydrogen or alkyl, and R″ isalkylsulfonylalkyl as defined herein.

“Alkylsulfonamidoalkyl means a group of the formula —R—NR′—SO₂—R″wherein R is alkylene, R′ is hydrogen or alkyl, and R″ is alkyl asdefined herein.

“Alkoxy” means a group —OR, wherein R is alkyl as defined herein.Examples of alkoxy moieties include, but are not limited to, methoxy,ethoxy, isopropoxy, and the like.

“Alkoxycarbonyl” means a group of the formula —C(O)—R wherein R isalkoxy as defined herein.

“Alkoxycarbonylaminoalkyl” means a group of the formula —R—NR′—R″wherein R is alkylene, R′ is hydrogen or alkyl, and R″ is alkoxycarbonylas defined herein.

“Alkoxycarbonylalkyl” means a group of the formula —R—C(O)—R′ wherein R′is alkoxy and R is alkylene as defined herein.

“Alkoxycarbonylalkylaminoalkyl” means a group of the formula —R—NR′—R″wherein R is alkylene, R′ is hydrogen or alkyl, and R″ is alkoxycarbonylalkyl as defined herein.

“Alkoxyalkyl” is a group of the formula —R—OR′ wherein R′ is alkyl and Ris alkylene as defined herein.

“Alkoxyalkylaminoalkyl” means a group of the formula —R—NR′—R″ wherein Ris alkylene, R′ is hydrogen or alkyl, and R″ is al coxyalkyl as definedherein.

“Amino” means a group —NRR′ wherein R and R′ each independently ishydrogen or alkyl as defined herein. “Amino” thus includes “alkylamino”and “dialkylamino”.

“Amidinyl” means a group of the formula:

wherein each R independently is hydrogen or alkyl as defined herein.“N-cyanoamidinyl” means a group of the formula

wherein R′ is cyano and R is hydrogen or alkyl as defined herein.

“Aminosulfonyl means a group —SO₂—R wherein R is —NR′— and R′ ishydrogen or alkyl as defined herein.

“Amidinylalkyl” means a group —R—R′ wherein R′ is amidinyl and R isalkylene as defined herein.

“Aminoalkyl” means a group —R—R′ wherein R′ is amino and R is alkyleneas defined herein. “Aminoalkyl” includes aminomethyl, aminoethyl,1-aminopropyl, 2-aminopropyl, and the like. The amino moiety of“aminoalkyl” may be substituted once or twice with alkyl to provide“alkylaminoalkyl” and “dialkylaminoalkyl” respectively.“Alkylaminoalkyl” includes methylaminomethyl, methylaminoethyl,methylaminopropyl, ethylaminoethyl and the like. “Dialkylaminoalkyl”includes dimethylaminomethyl, dimethylaminoethyl, dimethylaminopropyl,N-methyl-N-ethylaminoethyl, and the like.

“Alkylaminoalkyl” means a group of the formula —R—NR′—R″ wherein R′ ishydrogen or alkyl, R″ is alkyl, and R is alkylene as defined herein.“Dialkylaminoalkyl” is alkylaminoalkyl wherein R′ is alkyl.

“Aminocarbonyl” means a group of the formula —C(O)—R wherein R is aminoas defined herein.

“Aminocarbonylalkyl” means a group of the formula —R—C(O)—R′ wherein R′is amino and R is alkylene as defined herein.

“Aminocarbonylalkylaminoalkyl means a group of the formula —R—NR′—R”wherein R is alkylene, R′ is hydrogen or alkyl, and R″ isaminocarbonylalkyl as defined herein.

“Aminoalkylcarbonyl” means a group of the formula —C(O)—R—R′ wherein R′is amino and R is alkylene as defined herein.

“Aminoalkylcarbonylaminoalkyl” means a group of the formula —R—NR′—R″wherein R is alkylene, R′ is hydrogen or alkyl, and R″ isaminocarbonylalkyl as defined herein.

“Aminosulfonamidoalkyl” means a group of the formula —R—NR′—SO₂—R″wherein R is alkylene, R′ is hydrogen or alkyl, and R″ is amino asdefined herein.

“Aryl” means a monovalent cyclic aromatic hydrocarbon moiety consistingof a mono-, bi- or tricyclic aromatic ring. The aryl group can beoptionally substituted as defined herein. Examples of aryl moietiesinclude, but are not limited to, phenyl, naphthyl, naphthalenyl,phenanthryl, fluorenyl, indenyl, pentalenyl, azulenyl, oxydiphenyl,biphenyl, methylenediphenyl, aminodiphenyl, diphenylsulfidyl,diphenylsulfonyl, diphenylisopropylidenyl, benzodioxanyl, benzofuranyl,benzodioxylyl, benzopyranyl, benzoxazinyl, benzoxazinonyl,benzopiperadinyl, benzopiperazinyl, benzopyrrolidinyl, benzomorpholinyl,methylenedioxyphenyl, ethylenedioxyphenyl, and the like, includingpartially hydrogenated derivatives thereof.

“Arylene” means a divalent aryl radical wherein aryl is as definedherein. “Arylene” includes, for example, ortho-, meta- andpara-phenylene (1,2-phenylene, 1,3-phenylene and 1,4-phenylenerespectively), which may be optionally substituted as defined herein.

“Arylalkyl” and “Aralkyl”, which may be used interchangeably, mean aradical —R—R′ where R is an alkylene group and R′ is an aryl group asdefined herein; e.g., benzyl, phenylethyl,3-(3-chlorophenyl)-2-methylpentyl, and the like are examples ofarylalkyl.

“Cycloalkyl” means a saturated carbocyclic moiety consisting of mono- orbicyclic rings. Cycloalkyl can optionally be substituted with one ormore substituents, wherein each substituent is independently hydroxy,alkyl, alkoxy, halo, haloalkyl, amino, monoalkylamino, or dialkylamino,unless otherwise specifically indicated. Examples of cycloalkyl moietiesinclude, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, and the like, including partially unsaturatedderivatives thereof such as cyclohexenyl, cyclopentenyl, and the like.

“Cycloalkylalkyl” means a moiety of the formula —R—R′, where R isalkylene and R′ is cycloalkyl as defined herein.

“Guanidinyl” means a group of the formula

wherein each R independently is hydrogen or alkyl, R′ is hydrogen,alkyl, or phenyl, and R″ is hydrogen, alkyl or cyano. The phenyl moietyof “guanidinyl” may be optionally substituted as defined herein.“N-cyanoguanidinyl” means R″ in the formula for guanidinyl is cyano.

“Guanidinylalkyl” is a group —R—R′ wherein R′ is guanidinyl and R isalkylene as defined herein. “N-cyanoguanidinylalkyl means R′ isN-cyanoguanidinyl as defined herein.

“Guanidinylcarbonylalkyl” means a group of the formula —R—C(O)—R′wherein R′ is guanidinyl and R is alkylene as defined herein.

“Heteroalkyl” means an alkyl radical as defined herein wherein one, twoor three hydrogen atoms have been replaced with a substituentindependently selected from the group consisting of —OR^(a),—NR^(b)R^(c), and —S(O)_(n)R^(d) (where n is an integer from 0 to 2),with the understanding that the point of attachment of the heteroalkylradical is through a carbon atom, wherein R^(a) is hydrogen, acyl,alkyl, cycloalkyl, or cycloalkylalkyl; R^(b) and R^(c) are independentlyof each other hydrogen, acyl, alkyl, cycloalkyl, or cycloalkylalkyl; andwhen n is 0, R^(d) is hydrogen, alkyl, cycloalkyl, or cycloalkylalkyl,and when n is 1 or 2, R^(d) is alkyl, cycloalkyl, cycloalkylalkyl,amino, acylamino, monoalkylamino, or dialkylamino. Representativeexamples include, but are not limited to, methoxy, ethoxy,2-hydroxyethyl, 3-hydroxypropyl, 2-methoxyethyl, 3-methoxypropyl,2-hydroxy-1-hydroxymethylethyl, 2,3-dihydroxypropyl,1-hydroxymethylethyl, 3-hydroxybutyl, 2,3-dihydroxybutyl,2-hydroxy-1-methylpropyl, 2-aminoethyl, 3-aminopropyl,2-methylsulfonylethyl, aminosulfonylmethyl, aminosulfonylethyl,aminosulfonylpropyl, methylaminosulfonylmethyl,methylaminosulfonylethyl, methylaminosulfonylpropyl, and the like.

“Heteroaryl” means a monocyclic or bicyclic monovalent radical of 5 to12 ring atoms having at least one aromatic ring containing one, two, orthree ring heteroatoms selected from N, O, or S, the remaining ringatoms being C, with the understanding that the attachment point of theheteroaryl radical will be on an aromatic ring. The heteroaryl ring maybe optionally substituted as defined herein. Examples of heteroarylmoieties include, but are not limited to, imidazolyl, oxazolyl,isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl,pyrazinyl, thienyl, benzothienyl, thiophenyl, furanyl, pyranyl, pyridyl,pyridinyl, pyridazyl, pyrrolyl, pyrazolyl, pyrimidyl, quinolinyl,isoquinolinyl, benzofuryl, benzothiophenyl, benzothiopyranyl,benzimidazolyl, benzooxazolyl, benzooxadiazolyl, benzothiazolyl,benzothiadiazolyl, benzopyranyl, indolyl, isoindolyl, triazolyl,triazinyl, quinoxalinyl, purinyl, quinazolinyl, quinolizinyl,naphthyridinyl, pteridinyl, carbazolyl, azepinyl, diazepinyl, acridinyland the like, including partially hydrogenated derivatives thereof. Theaforementioned heteroaryl moieties may be partially saturated. Thus,“heteroaryl” includes “imidazolinyl”, tetrahydropyrimidinyl” and thelike.

“Heteroarylene” means a divalent heteroaryl radical wherein heteroarylis as defined herein. “Heteroarylene” may be optionally substituted asdefined herein. “Heteroarylene” includes, for example, indolylene,pyrimidinylene, and the like.

“Heteroarylaminoalkyl” means a group of the formula —R—NR′—R″ wherein Ris alkylene, R′ is hydrogen or alkyl, and R″ is heteroaryl as definedherein.

The terms “halo” and “halogen”, which may be used interchangeably, referto a substituent fluoro, chloro, bromo, or iodo.

“Haloalkyl” means alkyl as defined herein in which one or more hydrogenhas been replaced with same or different halogen. Exemplary haloalkylsinclude —CH₂Cl, —CH₂CF₃, —CH₂CCl₃, perfluoroalkyl (e.g., —CF₃), and thelike.

“Heterocycloamino” means a saturated ring wherein at least one ring atomis N, NH or N-alkyl and the remaining ring atoms form an alkylene group.

“Heterocyclyl” means a monovalent saturated moiety, consisting of one tothree rings, incorporating one, two, or three or four heteroatoms(chosen from nitrogen, oxygen or sulfur). The heterocyclyl ring may beoptionally substituted as defined herein. Examples of heterocyclylmoieties include, but are not limited to, piperidinyl, piperazinyl,homopiperazinyl, azepinyl, pyrrolidinyl, pyrazolidinyl, imidazolinyl,imidazolidinyl, pyridinyl, pyridazinyl, oxazolidinyl, isoxazolidinyl,morpholinyl, thiazolidinyl, isothiazolidinyl, quinuclidinyl, quinolinyl,isoquinolinyl, benzimidazolyl, thiadiazolylidinyl, benzothiazolidinyl,benzoazolylidinyl, dihydrofuryl, tetrahydrofuryl, dihydropyranyl,tetrahydropyranyl, thiamorpholinyl, thiamorpholinylsulfoxide,thiamorpholinylsulfone, dihydroquinolinyl, dihydrisoquinolinyl,tetrahydroquinolinyl, tetrahydrisoquinolinyl, and the like, includingpartially unsaturated derivatives thereof.

“Hydroxyalkyl” means an alkyl as defined herein that is substituted one,two or three times with hydroxy.

“Hydroxyalkylcarbonyl” means a group of the formula —C(O)—R—OH wherein Ris alkylene as defined herein.

“Hydroxyalkylcarbonylaminoalkyl” means a group of the formula —R—NR′—R″wherein R is alkylene, R′ is hydrogen or alkyl, and R″ ishydroxyalkylcarbonyl as defined herein.

“Hydroxyalkylaminoalkyl” means a group of the formula —R—NR′—R″ whereinR is alkylene, R′ is hydrogen or alkyl, and R″ is hydroxyalkyl asdefined herein.

“Imidazolinyl” means a group of the formula

and more preferably a group of the formula

wherein R is hydrogen or alkyl. “Imidazolinyl” may be interchangeablyused with “4,5-dihydro-1H-imidazol-2-yl”.

“Imidazolonyl” means a group of the formula

and more preferably a group of the formula

wherein R is hydrogen or alkyl.

“Imidazolonylaminoalkyl means a group of the formula —R—NR′—R” wherein Ris alkylene, R′ is hydrogen or alkyl, and R″ is imidazolonyl as definedherein.

“Imidazolinylalkyl” means a group —R—R′ wherein R′ is imidazolinyl asdefined herein and R is alkylene.

“Imidazolinylaminoalkyl” means a group —R—R′—R″ wherein R″ isimidazolinyl as defined herein, R′ is amino, and R is alkylene. Theamino moiety of “imidazolinylaminoalkyl” may be optionally substitutedwith alkyl.

“Imidazolylcarbonyl” means a group of the formula

wherein R is hydrogen or alkyl as defined herein.

“Imidazolinylaminoalkyl” means a group of the formula —R—NR′—R″ whereinR is alkylene, R′ is hydrogen or alkyl, and R″ is imidazolinyl asdefined herein.

“Imidazolylaminoalkyl” means a group of the formula —R—NR′—R″ wherein Ris alkylene, R′ is hydrogen or alkyl as defined herein, and R″ isimidazolyl.

“Imidazolinylalkyl” is a group of the formula —R—R″ wherein R isalkylene and R″ is imidazolinyl as defined herein

“Imidazolinylcarbonylaminoalkyl” means a group of the formula—R—C(O)—NR′—R″ wherein R is alkylene, R′ is hydrogen or alkyl, and R″ isimidazolinyl as defined herein.

“Pyrimidinylaminoalkyl” means a group —R—R′—R″ wherein R″ is pyrimidinyl(preferably pyrimidin-2-yl), R′ is amino, and R is alkylene. Thepyrimidinyl moiety of “pyrimidinylaminoalkyl” may be optionallysubstituted as defined herein, and the amino moiety of“pyrimidinylaminoalkyl” may be optionally substituted with alkyl.

“Pyrrolylcarbonyl” means a group of the formula

wherein R is hydrogen or alkyl as defined herein.

“Pyrrolylcarbonylaminoalkyl” means a group of the formula —R—NR′—R″wherein R is alkylene, R′ is hydrogen or alkyl, and R″ ispyrrolylcarbonyl as defined herein.

“Pyrrolidinylcarbonyl” means a group of the formula

wherein R is hydrogen or alkyl as defined herein.

“Pyrrolidinylcarbonylaminoalkyl” means a group of the formula —R—NR′—R″wherein R is alkylene, R′ is hydrogen or alkyl, and R″ ispyrrolidinylcarbonyl as defined herein.

“Tetrahydropyrimidinyl” means 1,4,5,6-tetrahydropyrimidinyl, preferably1,4,5,6-tetrahydropyrimidin-2-yl, and may be optionally substituted asdefined herein. “Tetrahydropyrimidinyl” includes5,5-dimethyl-1,4,5,6-tetrahydropyrimidin-2-yl.

“Tetrahydropyrimidinylaminoalkyl” means a group —R—NR′—R″ wherein R″ istetrahydropyrimidinyl, R′ is hydrogen or alkyl, and R is alkylene asdefined herein.

“Urea” or “ureyl”, which may be used interchangeably, means a group ofthe formula:

wherein each R is independently is hydrogen or alkyl.

“Urealkyl” means a group R—R′ wherein R′ is urea and R is alkylene asdefined herein.

“Optionally substituted”, when used in association with “aryl”, phenyl“,“heteroaryl”, or “heterocyclyl”, means an aryl, phenyl, heteroaryl, orheterocyclyl which is optionally substituted independently with one tofour substituents, preferably one or two substituents selected fromalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, hydroxyalkyl, halo,nitro, cyano, hydroxy, alkoxy, amino, acylamino, mono-alkylamino,di-alkylamino, haloalkyl, haloalkoxy, heteroalkyl, —COR (where R ishydrogen, alkyl, phenyl or phenylalkyl), —(CR′R″)_(n)—COOR (where n isan integer from 0 to 5, R′ and R″ are independently hydrogen or alkyl,and R is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl orphenylalkyl), or —(CR′R″)_(n)—CONR^(a)R^(b) (where n is an integer from0 to 5, R′ and R″ are independently hydrogen or alkyl, and R^(a) andR^(b) are, independently of each other, hydrogen, alkyl, cycloalkyl,cycloalkylalkyl, phenyl or phenylalkyl.

“Leaving group” means the group with the meaning conventionallyassociated with it in synthetic organic chemistry, i.e., an atom orgroup displaceable under substitution reaction conditions. Examples ofleaving groups include, but are not limited to, halogen, alkane- orarylenesulfonyloxy, such as methanesulfonyloxy, ethanesulfonyloxy,thiomethyl, benzenesulfonyloxy, tosyloxy, and thienyloxy,dihalophosphinoyloxy, optionally substituted benzyloxy, isopropyloxy,acyloxy, and the like.

“Modulator” means a molecule that interacts with a target. Theinteractions include, but are not limited to, agonist, antagonist, andthe like, as defined, herein.

“Optional” or “optionally” means that the subsequently described eventor circumstance may but need not occur, and that the descriptionincludes instances where the event or circumstance occurs and instancesin which it does not.

“Disease state” means any disease, condition, symptom, or indication.

“Inert organic solvent” or “inert solvent” means the solvent is inertunder the conditions of the reaction being described in conjunctiontherewith, including for example, benzene, toluene, acetonitrile,tetrahydrofuran, N,N-dimethylformamide, chloroform, methylene chlorideor dichloromethane, dichloroethane, diethyl ether, ethyl acetate,acetone, methyl ethyl ketone, methanol, ethanol, propanol, isopropanol,tert-butanol, dioxane, pyridine, and the like. Unless specified to thecontrary, the solvents used in the reactions of the present inventionare inert solvents.

“Pharmaceutically acceptable” means that which is useful in preparing apharmaceutical composition that is generally safe, non-toxic, andneither biologically nor otherwise undesirable and includes that whichis acceptable for veterinary as well as human pharmaceutical use.

“Pharmaceutically acceptable salts” of a compound means salts that arepharmaceutically acceptable, as defined herein, and that possess thedesired pharmacological activity of the parent compound. Such saltsinclude:

-   -   acid addition salts formed with inorganic acids such as        hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,        phosphoric acid, and the like; or formed with organic acids such        as acetic acid, benzenesulfonic acid, benzoic, camphorsulfonic        acid, citric acid, ethanesulfonic acid, fumaric acid,        glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid,        hydroxynaphtoic acid, 2-hydroxyethanesulfonic acid, lactic acid,        maleic acid, malic acid, malonic acid, mandelic acid,        methanesulfonic acid, muconic acid, 2-naphthalenesulfonic acid,        propionic acid, salicylic acid, succinic acid, tartaric acid,        p-toluenesulfonic acid, trimethylacetic acid, and the like; or    -   salts formed when an acidic proton present in the parent        compound either is replaced by a metal ion, e.g., an alkali        metal ion, an alkaline earth ion, or an aluminum ion; or        coordinates with an organic or inorganic base. Acceptable        organic bases include diethanolamine, ethanolamine,        N-methylglucamine, triethanolamine, tromethamine, and the like.    -   Acceptable inorganic bases include aluminum hydroxide, calcium        hydroxide, potassium hydroxide, sodium carbonate and sodium        hydroxide.

The preferred pharmaceutically acceptable salts are the salts formedfrom acetic acid, hydrochloric acid, sulphuric acid, methanesulfonicacid, maleic acid, phosphoric acid, tartaric acid, citric acid, sodium,potassium, calcium, zinc, and magnesium.

It should be understood that all references to pharmaceuticallyacceptable salts include solvent addition forms (solvates) or crystalforms (polymorphs) as defined herein, of the same acid addition salt.

The terms “pro-drug” and “prodrug”, which may be used interchangeablyherein, refer to any compound which releases an active parent drugaccording to formula I in vivo when such prodrug is administered to amammalian subject. Prodrugs of a compound of formula I are prepared bymodifying one or more functional group(s) present in the compound offormula I in such a way that the modification(s) may be cleaved in vivoto release the parent compound. Prodrugs include compounds of formula Iwherein a hydroxy, amino, or sulfhydryl group in a compound of Formula Iis bonded to any group that may be cleaved in vivo to regenerate thefree hydroxyl, amino, or sulfhydryl group, respectively. Examples ofprodrugs include, but are not limited to, esters (e.g., acetate,formate, and benzoate derivatives), carbamates (e.g.,N,N-dimethylaminocarbonyl) of hydroxy functional groups in compounds offormula I, N-acyl derivatives (e.g. N-acetyl) N-Mannich bases, Schiffbases and enaminones of amino functional groups, oximes, acetals, ketalsand enol esters of ketone and aldehyde functional groups in compounds ofFormula I, and the like, see Bundegaard, H. “Design of Prodrugs” p 1-92,Elesevier, New York-Oxford (1985), and the like.

“Protective group” or “protecting group” means the group whichselectively blocks one reactive site in a multifunctional compound suchthat a chemical reaction can be carried out selectively at anotherunprotected reactive site in the meaning conventionally associated withit in synthetic chemistry. Certain processes of this invention rely uponthe protective groups to block reactive nitrogen and/or oxygen atomspresent in the reactants. For example, the terms “amino-protectinggroup” and “nitrogen protecting group” are used interchangeably hereinand refer to those organic groups intended to protect the nitrogen atomagainst undesirable reactions during synthetic procedures. Exemplarynitrogen protecting groups include, but are not limited to,trifluoroacetyl, acetamido, benzyl (Bn), benzyloxycarbonyl(carbobenzyloxy, CBZ), p-methoxybenzyloxycarbonyl,p-nitrobenzyloxycarbonyl, tert-butoxycarbonyl (BOC), and the like. Thoseskilled in the art know how to choose a group for the ease of removaland for the ability to withstand the following reactions.

“Solvates” means solvent addition forms that contain eitherstoichiometric or non stoichiometric amounts of solvent. Some compoundshave a tendency to trap a fixed molar ratio of solvent molecules in thecrystalline solid state, thus forming a solvate. If the solvent is waterthe solvate formed is a hydrate, when the solvent is alcohol, thesolvate formed is an alcoholate. Hydrates are formed by the combinationof one or more molecules of water with one of the substances in whichthe water retains its molecular state as H₂O, such combination beingable to form one or more hydrate.

“Subject” means mammals and non-mammals. Mammals means any member of themammalia class including, but not limited to, humans; non-human primatessuch as chimpanzees and other apes and monkey species; farm animals suchas cattle, horses, sheep, goats, and swine; domestic animals such asrabbits, dogs, and cats; laboratory animals including rodents, such asrats, mice, and guinea pigs; and the like. Examples of non-mammalsinclude, but are not limited to, birds, and the like. The term “subject”does not denote a particular age or sex.

“Therapeutically effective amount” means an amount of a compound that,when administered to a subject for treating a disease state, issufficient to effect such treatment for the disease state. The“therapeutically effective amount” will vary depending on the compound,disease state being treated, the severity or the disease treated, theage and relative health of the subject, the route and form ofadministration, the judgement of the attending medical or veterinarypractitioner, and other factors.

The terms “those defined above” and “those defined herein” whenreferring to a variable incorporates by reference the broad definitionof the variable as well as preferred, more preferred and most preferreddefinitions, if any.

“Treating” or “treatment” of a disease state includes:

-   -   (i) preventing the disease state, i.e. causing the clinical        symptoms of the disease state not to develop in a subject that        may be exposed to or predisposed to the disease state, but does        not yet experience or display symptoms of the disease state.    -   (ii) inhibiting the disease state, i.e., arresting the        development of the disease state or its clinical symptoms, or    -   (iii) relieving the disease state, i.e., causing temporary or        permanent regression of the disease state or its clinical        symptoms.

The terms “treating”, “contacting” and “reacting” when referring to achemical reaction means adding or mixing two or more reagents underappropriate conditions to produce the indicated and/or the desiredproduct. It should be appreciated that the reaction which produces theindicated and/or the desired product may not necessarily result directlyfrom the combination of two reagents which were initially added, i.e.,there may be one or more intermediates which are produced in the mixturewhich ultimately leads to the formation of the indicated and/or thedesired product.

Nomenclature

In general, the nomenclature used in this Application is based onAUTONOM™ v.4.0, a Beilstein Institute computerized system for thegeneration of IUPAC systematic nomenclature.

Chemical structures shown herein were prepared using ISIS® version 2.2.Any open valency appearing on a carbon, oxygen or nitrogen atom in thestructures herein indicates the presence of a hydrogen.

Compounds of the Invention

The invention provides compounds of the formula I:

It should be understood that the scope of this invention encompasses notonly the various isomers which may exist but also the various mixture ofisomers which may be formed. Furthermore, the scope of the presentinvention also encompasses solvates and salts of compounds of formula I:

-   or a pharmaceutically acceptable salt thereof,-   wherein:

m is from 0 to 3;

p is from 1 to 3;

q is 0, 1 or 2;

Ar is optionally substituted aryl or optionally substituted heteroaryl;

is an optional bond;

each R¹ is independently halo, alkyl, haloalkyl, alkoxy, hydroxy,heteroalkyl, cyano, —S(O)_(t)—R^(a), —C(═O)—NR^(b)R^(c),—SO₂—NR^(b)R^(c), —N(R^(d))—C(═O)—R^(e), or —C(═O)—R^(e), where t isfrom 0 to 2, R^(a), R^(b), R^(c), R^(d) and R^(e) each independently ishydrogen or alkyl, and R^(f) is hydrogen, alkyl, alkoxy or hydroxy;

R² is

n is from 1 to 3;

R³ and R⁴ each independently is hydrogen or alkyl, or R³ and R⁴ togethermay form ═O or ═NR^(f) wherein R^(f) is hydrogen or alkyl; and

one of R⁵ and R⁶ is hydrogen or alkyl and the other is: hydrogen; alkyl;amidinyl; aminocarbonyl; alkylcarbonyl; alkoxycarbonyl;aminocarbonylalkyl; aminoalkylcarbonyl; alkoxycarbonylalkyl;imidazolonyl; imidazolylcarbonyl; pyrrolylcarbonyl;pyrrolidinylcarbonyl; N-cyanoamidinyl; alkylsulfonyl;hydroxyalkylcarbonyl; aminosulfonyl; hydroxyalkyl; alkoxalkyl;alkylsulfonylalkyl; or optionally substituted heteroaryl; or

R⁵ and R⁶ together with the nitrogen to which they are attached may forman amidinyl group, a urea group, a guanidinyl group or a five- orsix-membered heteroaryl or heterocyclyl ring that is optionallysubstituted and which optionally includes an additional heteroatomselected from O, N and S; or

one of R⁵ and R⁶ and one of R³ and R⁴ together with the atoms to whichthey are attached may form a five- or six-membered ring that optionallyincludes an additional heteroatom selected from O, N and S.

In many embodiments of formula I, p is 1 or 2. Preferably p is 2.

In many embodiments of formula I, q is 2.

In many embodiments of formula I, m is 0 or 1.

In certain embodiments of formula I, R¹ is halo.

In certain embodiments of formula I, the group Ar—S(O)_(q)— is locatedat the 6- or 7-position of the tetralin ring system.

In certain embodiments of formula I, the group Ar—S(O)_(q)— is locatedat the 6-position of the tetralin ring system.

In certain embodiments of formula I, m is 0 or 1 and R¹ is located atthe 8-position of the tetralin ring system.

In certain embodiments of formula I, n is 1.

In certain embodiments of formula I, n is 2.

In certain embodiments of formula I, n is 3.

In certain embodiments of formula I, R³ and R⁴ are hydrogen.

In certain embodiments of formula I, one of R⁵ and R⁶ is hydrogen andthe other is alkyl.

In certain embodiments of formula I, R⁵ and R⁶ are hydrogen.

In certain embodiments of formula I, one of R⁵ and R⁶ is hydrogen oralkyl and the other is: alkyl; amidinyl; aminocarbonyl; alkylcarbonyl;alkoxycarbonyl; aminocarbonylalkyl; aminoalkylcarbonyl;alkoxycarbonylalkyl; imidazolonyl; imidazolylcarbonyl; pyrrolylcarbonyl;pyrrolidinylcarbonyl; N-cyanoamidinyl; alkylsulfonyl;hydroxyalkylcarbonyl; aminosulfonyl; hydroxyalkyl; or alkoxalkyl.

In certain embodiments of formula I, one of R⁵ and R⁶ is hydrogen oralkyl and the other is: hydrogen; alkyl; amidinyl; aminocarbonyl;alkylcarbonyl; alkoxycarbonyl; aminocarbonylalkyl; aminoalkylcarbonyl;alkoxycarbonylalkyl; imidazolonyl; imidazolylcarbonyl; pyrrolylcarbonyl;pyrrolidinylcarbonyl; N-cyanoamidinyl; alkylsulfonyl;hydroxyalkylcarbonyl; aminosulfonyl; hydroxyalkyl; alkoxalkyl; oroptionally substituted heteroaryl.

In certain embodiments of formula I, one of R⁵ and R⁶ is hydrogen andthe other is: hydrogen; alkyl; amidinyl; aminocarbonyl; alkylcarbonyl;alkoxycarbonyl; aminocarbonylalkyl; aminoalkylcarbonyl;alkoxycarbonylalkyl; alkylsulfonyl; or hydroxyalkylcarbonyl.

In certain embodiments of formula I, one of R⁵ and R⁶ is hydrogen andthe other is heteroaryl selected from benzothiazolyl, indolyl, thienyl,furanyl, pyridinyl, pyrimdinyl, pyrrolyl, pyrazolyl and imidazolyl, eachoptionally substituted.

In certain embodiments of formula I, one of R⁵ and R⁶ is hydrogen andthe other is heteroaryl selected from pyrimidinyl, benzothiazol-2-yl,and 5,5-dimethyl-1,4,5,6-tetrahydropyrimidinyl.

In certain embodiments of formula I, R⁵ and R⁶ together with thenitrogen to which they are attached form an amidinyl group.

In certain embodiments of formula I, R⁵ and R⁶ together with thenitrogen to which they are attached form a guanidinyl group.

In certain embodiments of formula I, R⁵ and R⁶ together with thenitrogen to which they are attached form a urea group.

In certain embodiments of formula I, R³ and R⁴ together with thenitrogen to which they are attached form ═NR^(f) wherein R^(f) ishydrogen.

In certain embodiments of formula I, R³ and R⁴ together with thenitrogen to which they are attached form ═O.

In certain embodiments of formula I, one of R⁵ and R⁶ and one of R³ andR⁴ together with the atoms to which they are attached form animidazolinyl ring.

In certain embodiments of formula I, R⁵ and R⁶ together with thenitrogen to which they are attached form or a five- or six-memberedheteroaryl ring that is optionally substituted and which optionallyincludes an additional nitrogen heteroatom.

In certain embodiments of formula I, R⁵ and R⁶ together with thenitrogen to which they are attached form or a five-, or six-memberedheteroaryl ring selected from pyridinyl, pyrimidinyl, pyrrolyl,imidazolyl or pyrazolyl, each optionally substituted.

In certain embodiments of formula I, R⁵ and R⁶ together with thenitrogen to which they are attached form they are attached form or afive- or six-membered heterocyclic ring that is optionally substitutedand which optionally includes an additional heteroatom selected from O,N and S.

In certain embodiments of formula I, R⁵ and R⁶ together with thenitrogen to which they are attached form they are attached form or afive- or six-membered heterocyclic ring selected from pyrrolidinyl,piperidinyl, piperazinyl, morpholinyl, azepinyl and diazepinyl.

In certain embodiments of formula I, Ar is optionally substitutedphenyl.

In certain embodiments of formula I, Ar is 2-halophenyl or 3-halopheny.

In certain embodiments of formula I, Ar is heteroaryl.

In certain embodiments of formula I, Ar is heteroaryl selected fromindolyl, pyrrolyl, imidazolyl, pyrazolyl, benzimidazolyl, thienyl,furanyl, pyridinyl and pyrimidinyl, each optionally substituted.

In certain embodiments of formula I, Ar is heteroaryl selected fromindolyl, pyrrolyl, imidazolyl, pyrazolyl, and benzimidazolyl, eachoptionally substituted.

In certain embodiments of formula I, Ar is heteroaryl selected fromindol-3-yl, pyrrol-3-yl, 1-methylimidazol-2-yl, imidazol-2-yl,pyrazol-4-yl, benzimidazol-4-yl, 6-fluoroindol-3-yl, 1-methylpyrrol-3-yland 6-fluorobenzimidazol-4-yl.

In certain embodiments of formula I, one of R⁵ and R⁶ and one of R³ andR⁴ together with the atoms to which they are attached form animidazolinyl ring.

In certain embodiments of formula I, p is 2 and q is 2.

In certain embodiments of formula I, p is 2, q is 2 and m is 0 or 1.

In certain embodiments of formula I, p is 2, q is 2, m is 0 or 1, and nis 1.

In certain embodiments of formula I, p is 2, q is 2, m is 0 or 1, n is1, and R³ and R⁴ are hydrogen.

In certain embodiments of formula I, p is 2, q is 2, m is 0 or 1, n is1, R³ and R⁴ are hydrogen, one of R⁵ and R⁶ is hydrogen or alkyl, andthe other is: alkyl; amidinyl; aminocarbonyl; alkylcarbonyl;alkoxycarbonyl; aminocarbonylalkyl; aminoalkylcarbonyl;alkoxycarbonylalkyl; imidazolonyl; imidazolylcarbonyl; pyrrolylcarbonyl;pyrrolidinylcarbonyl; N-cyanoamidinyl; alkylsulfonyl;hydroxyalkylcarbonyl; aminosulfonyl; hydroxyalkyl; alkoxalkyl; oroptionally substituted heteroaryl.

In certain embodiments of formula I, p is 2, q is 2, m is 0 or 1, n is1, R³ and R⁴ are hydrogen, one of R⁵ and R⁶ is hydrogen and the otheris: hydrogen; alkyl; amidinyl; aminocarbonyl; alkylcarbonyl;alkoxycarbonyl; aminocarbonylalkyl; aminoalkylcarbonyl;alkoxycarbonylalkyl; alkylsulfonyl; or hydroxyalkylcarbonyl.

In certain embodiments of formula I, p is 2, q is 2, m is 0 or 1, n is1, R³ and R⁴ are hydrogen, one of R⁵ and R⁶ is hydrogen and the other isalkyl.

In certain embodiments of formula I, p is 2, q is 2, m is 0 or 1, and R²is: aminoalkyl; alkylaminoalkyl; dialkylaminoalkyl;imidazolinylaminoalkyl; imidazolinylalkyl, guanidinylalkyl;tetrahydropyrimidinylaminoalkyl; amidinylalkyl; urealkyl; amidinyl;heteroarylaminoalkyl; imidazolylaminoalkyl; guanidinylcarbonylalkyl;imidazolonylaminoalkyl; imidazolinylcarbonylaminoalkyl;aminocarbonylalkyl; pyrrolylcarbonylaminoalkyl;aminoalkylcarbonylaminoalkyl; alkoxycarbonylalkylaminoalkyl;N-cyanoguanidinylalkyl; alkylcarbonylaminoalkyl;aminocarbonylalkylaminoalkyl; pyrrolidinylcarbonylaminoalkyl;alkylsulfonamidoalkyl; aminosulfonamidoalkyl; alkoxycarbonylaminoalkyl;hydroxyalkylcarbonylaminoalkyl; hydroxyalkylaminoalkyl;alkoxyalkylaminoalkyl; or alkylsulfonylalkylaminoalkyl.

In certain embodiments of formula I, p is 2, q is 2, m is 0 or 1, and R²is: aminoalkyl; alkylaminoalkyl; dialkylaminoalkyl; guanidinylalkyl;amidinylalkyl; urealkyl; amidinyl; guanidinylcarbonylalkyl;aminocarbonylalkyl; aminoalkylcarbonylaminoalkyl;alkylcarbonylaminoalkyl; aminocarbonylalkylaminoalkyl; oralkoxycarbonylaminoalkyl.

In certain embodiments of formula I, p is 2, q is 2, m is 0 or 1, and R²is:

wherein R^(g) is hydrogen, alkyl, optionally substituted phenyl oroptionally substituted pyrimidinyl, R^(h), R^(i), R^(j) and R^(k) ineach independent occurrence is hydrogen or alkyl, and R^(m) is hydrogen,alkyl or —NR^(h)R^(i).

In certain embodiments of formula I, p is 2, q is 2, m is 0 or 1, and R²is:

wherein R^(g), R^(h), R^(i) and R^(j) are hydrogen or alkyl.

In certain embodiments of formula I, p is 2, q is 2, m is 0 or 1, n is1, R³ and R⁴ are hydrogen, one of R⁵ and R⁶ is hydrogen or alkyl, andthe other is:

wherein R^(g) is hydrogen, alkyl, optionally substituted phenyl oroptionally substituted pyrimidinyl, R^(h), R^(i), R^(j) and R^(k) ineach independent occurrence is hydrogen or alkyl, and R^(m) is hydrogen,alkyl or —NR^(h)R^(i).

In certain embodiments of formula I, p is 2, q is 2, m is 0 or 1, n is1, R³ and R⁴ are hydrogen, one of R⁵ and R⁶ is hydrogen or alkyl, andthe other is:

wherein R^(g), R^(h), R^(i) and R^(j) are hydrogen or alkyl.

In certain embodiments of formula I, p is 2, q is 2, m is 0 or 1, n is 1or 2, and R³ and R⁴ together with the nitrogen to which they areattached form ═NR^(f) wherein R^(f) is hydrogen, and wherein R⁵ and R⁶are hydrogen.

In certain embodiments of formula I, p is 2, q is 2, m is 0 or 1, n isfor 2, and R³ and R⁴ together with the nitrogen to which they areattached form ═O.

In certain embodiments of formula I, p is 2, q is 2, m is 0 or 1, and nis 2.

In certain embodiments of formula I, p is 2, q is 2, m is 0 or 1, n is2, and R³ and R⁴ are hydrogen.

In certain embodiments of formula I, p is 2, q is 2, m is 0 or 1, n is2, R³ and R⁴ are hydrogen, one of R⁵ and R⁶ is hydrogen or alkyl, andthe other is: hydrogen; alkyl; amidinyl; aminocarbonyl; alkylcarbonyl;alkoxycarbonyl; aminocarbonylalkyl; aminoalkylcarbonyl;alkoxycarbonylalkyl; imidazolonyl; imidazolylcarbonyl; pyrrolylcarbonyl;pyrrolidinylcarbonyl; N-cyanoamidinyl; alkylsulfonyl;hydroxyalkylcarbonyl; aminosulfonyl; hydroxyalkyl; alkoxalkyl; oroptionally substituted heteroaryl.

In certain embodiments of formula I, p is 2, q is 2, m is 0 or 1, n is2, R³ and R⁴ are hydrogen, one of R⁵ and R⁶ is hydrogen and the otheris: hydrogen; alkyl; amidinyl; aminocarbonyl; alkylcarbonyl;alkoxycarbonyl; aminocarbonylalkyl; aminoalkylcarbonyl;alkoxycarbonylalkyl; alkylsulfonyl; or hydroxyalkylcarbonyl.

In certain embodiments of formula I, p is 2, q is 2, m is 0 or 1, n is2, R³ and R⁴ are hydrogen, one of R⁵ and R⁶ is hydrogen and the other isalkyl.

In certain embodiments of formula I, p is 2, q is 2, m is 0 or 1, n is2, R³ and R⁴ are hydrogen, one of R⁵ and R⁶ is hydrogen or alkyl, andthe other is:

wherein R^(g) is hydrogen, alkyl, optionally substituted phenyl oroptionally substituted pyrimidinyl, R^(h), R^(i), R^(j) and R^(k) ineach independent occurrence is hydrogen or alkyl, and R^(m) is hydrogen,alkyl or —NR^(h)R^(i).

In certain embodiments of formula I, p is 2, q is 2, m is 0 or 1, n is2, R³ and R⁴ are hydrogen, one of R⁵ and R⁶ is hydrogen or alkyl, andthe other is:

wherein R^(g), R^(h), R^(i) and R^(j) are hydrogen or alkyl.

In certain embodiments of formula I, p is 2, q is 2, m is 0 or 1, and nis 3.

In certain embodiments of formula I, p is 2, q is 2, m is 0 or 1, n is1, and R³ and R⁴ are hydrogen.

In certain embodiments of formula I, p is 2, q is 2, m is 0 or 1, n is3, R³ and R⁴ are hydrogen, one of R⁵ and R⁶ is hydrogen or alkyl, andthe other is: hydrogen; alkyl; amidinyl; aminocarbonyl; alkylcarbonyl;alkoxycarbonyl; aminocarbonylalkyl; aminoalkylcarbonyl;alkoxycarbonylalkyl; imidazolonyl; imidazolylcarbonyl; pyrrolylcarbonyl;pyrrolidinylcarbonyl; N-cyanoamidinyl; alkylsulfonyl;hydroxyalkylcarbonyl; aminosulfonyl; hydroxyalkyl; alkoxalkyl; oroptionally substituted heteroaryl.

In certain embodiments of formula I, p is 2, q is 2, m is 0 or 1, n is3, R³ and R⁴ are hydrogen, one of R⁵ and R⁶ is hydrogen and the otheris: hydrogen; alkyl; amidinyl; aminocarbonyl; alkylcarbonyl;alkoxycarbonyl; aminocarbonylalkyl; aminoalkylcarbonyl;alkoxycarbonylalkyl; alkylsulfonyl; or hydroxyalkylcarbonyl.

In certain embodiments of formula I, p is 2, q is 2, m is 0 or 1, n is3, R³ and R⁴ are hydrogen, one of R⁵ and R⁶ is hydrogen or alkyl, andthe other is:

wherein R⁸ is hydrogen, alkyl, optionally substituted phenyl oroptionally substituted pyrimidinyl, R^(h), R^(i), R^(j) and R^(k) ineach independent occurrence is hydrogen or alkyl, and R^(m) is hydrogen,alkyl or —NR^(h)R^(i).

In certain embodiments of formula I, p is 2, q is 2, m is 0 or 1, n is3, R³ and R⁴ are hydrogen, one of R⁵ and R⁶ is hydrogen or alkyl, andthe other is:

wherein R^(g), R^(h), R^(i) and R^(j) are hydrogen or alkyl.

In certain embodiments, the compounds of the invention may be of formulaII:

wherein m, Ar, R¹ and R² are as defined herein.

In certain embodiments, the compounds of the invention may be of formulaIIa:

wherein m, Ar, R¹ and R² are as defined herein.

In certain embodiments, the compounds of the invention may be of formulaIIb:

wherein m, Ar, R¹ and R² are as defined herein.

In many embodiments of any of formulas II, IIa or IIb, m is 0 or 1.

In certain embodiments of any of formulas II, IIa or IIb, R¹ is halo.

In certain embodiments of any of formulas II, IIa or IIb, the groupAr—SO₂— is located at the 6- or 7-position of the tetralin ring system.

In certain embodiments of any of formulas II, IIa or IIb, the groupAr—SO₂— is located at the 6-position of the tetralin ring system.

In certain embodiments of any of formulas II, IIa or IIb, m is 0 or 1and R¹ is located at the 8-position of the tetralin ring system.

In certain embodiments of any of formulas II, IIa or IIb, n is 1.

In certain embodiments of any of formulas II, IIa or IIb, n is 2.

In certain embodiments of any of formulas II, IIa or IIb, n is 3.

In certain embodiments of any of formulas II, IIa or IIb, R³ and R⁴ arehydrogen.

In certain embodiments of any of formulas II, IIa or IIb, one of R⁵ andR⁶ is hydrogen and the other is alkyl.

In certain embodiments of any of formulas II, IIa or IIb, R⁵ and R⁶ arehydrogen.

In certain embodiments of any of formulas II, IIa or IIb, one of R⁵ andR⁶ is hydrogen or alkyl and the other is: alkyl; amidinyl;aminocarbonyl; alkylcarbonyl; alkoxycarbonyl; aminocarbonylalkyl;aminoalkylcarbonyl; alkoxycarbonylalkyl; imidazolonyl;imidazolylcarbonyl; pyrrolylcarbonyl; pyrrolidinylcarbonyl;N-cyanooxamidinyl; alkylsulfonyl; hydroxyalkylcarbonyl; aminosulfonyl;hydroxyalkyl; or alkoxalkyl.

In certain embodiments of any of formulas II, IIa or IIb, one of R⁵ andR⁶ is hydrogen or alkyl and the other is: hydrogen; alkyl; amidinyl;aminocarbonyl; alkylcarbonyl; alkoxycarbonyl; aminocarbonylalkyl;aminoalkylcarbonyl; alkoxycarbonylalkyl; imidazolonyl;imidazolylcarbonyl; pyrrolylcarbonyl; pyrrolidinylcarbonyl;N-cyanoamidinyl; alkylsulfonyl; hydroxyalkylcarbonyl; aminosulfonyl;hydroxyalkyl; alkoxalkyl; or optionally substituted heteroaryl.

In certain embodiments of any of formulas II, IIa or IIb, one of R⁵ andR⁶ is hydrogen and the other is: hydrogen; alkyl; amidinyl;aminocarbonyl; alkylcarbonyl; alkoxycarbonyl; aminocarbonylalkyl;aminoalkylcarbonyl; alkoxycarbonylalkyl; alkylsulfonyl; orhydroxyalkylcarbonyl.

In certain embodiments of any of formulas II, IIa or IIb, one of R⁵ andR⁶ is hydrogen and the other is heteroaryl selected from benzothiazolyl,indolyl, thienyl, furanyl, pyridinyl, pyrimdinyl, pyrrolyl, pyrazolyland imidazolyl, each optionally substituted.

In certain embodiments of any of formulas II, IIa or IIb, one of R⁵ andR⁶ is hydrogen and the other is heteroaryl selected from pyrimidinyl,benzothiazol-2-yl, and 5,5-dimethyl-1,4,5,6-tetrahydropyrimidinyl.

In certain embodiments of any of formulas II, IIa or IIb, R⁵ and R⁶together with the nitrogen to which they are attached form an amidinylgroup.

In certain embodiments of any of formulas II, IIa or IIb, R⁵ and R⁶together with the nitrogen to which they are attached form a guanidinylgroup.

In certain embodiments of any of formulas II, IIa or IIb, R⁵ and R⁶together with the nitrogen to which they are attached form a urea group.

In certain embodiments of any of formulas II, IIa or IIb, R³ and R⁴together with the nitrogen to which they are attached form ═NR^(f)wherein R^(f) is hydrogen.

In certain embodiments of any of formulas II, IIa or IIb, R³ and R⁴together with the nitrogen to which they are attached form ═O.

In certain embodiments of any of formulas II, IIa or IIb, one of R⁵ andR⁶ and one of R³ and R⁴ together with the atoms to which they areattached form an imidazolinyl ring.

In certain embodiments of any of formulas II, IIa or IIb, R⁵ and R⁶together with the nitrogen to which they are attached form or a five- orsix-membered heteroaryl ring that is optionally substituted and whichoptionally includes an additional nitrogen heteroatom.

In certain embodiments of any of formulas II, IIa or IIb, R⁵ and R⁶together with the nitrogen to which they are attached form or a five- orsix-membered heteroaryl ring selected from pyridinyl, pyrimidinyl,pyrrolyl, imidazolyl or pyrazolyl, each optionally substituted.

In certain embodiments of any of formulas II, IIa or IIb, R⁵ and R⁶together with the nitrogen to which they are attached form they areattached form or a five- or six-membered heterocyclic ring that isoptionally substituted and which optionally includes an additionalheteroatom selected from O, N and S.

In certain embodiments of any of formulas II, IIa or IIb, R⁵ and R⁶together with the nitrogen to which they are attached form they areattached form or a five- or six-membered heterocyclic ring selected frompyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azepinyl anddiazepinyl.

In certain embodiments of any of formulas II, IIa or IIb, Ar isoptionally substituted phenyl.

In certain embodiments of any of formulas II, IIa or IIb, Ar is2-halophenyl or 3-halopheny.

In certain embodiments of any of formulas II, IIa or IIb, Ar isheteroaryl.

In certain embodiments of any of formulas II, IIa or IIb, Ar isheteroaryl selected from indolyl, pyrrolyl, imidazolyl, pyrazolyl,benzimidazolyl, thienyl, furanyl, pyridinyl and pyrimidinyl, eachoptionally substituted.

In certain embodiments of any of formulas II, IIa or IIb, Ar isheteroaryl selected from indolyl, pyrrolyl, imidazolyl, pyrazolyl, andbenzimidazolyl, each optionally substituted.

In certain embodiments of any of formulas II, IIa or IIb, Ar isheteroaryl selected from indol-3-yl, pyrrol-3-yl, 1-methylimidazol-2-yl,imidazol-2-yl, pyrazol-4-yl, benzimidazol-4-yl, 6-fluoroindol-3-yl,1-methylpyrrol-3-yl and 6-fluorobenzimidazol-4-yl.

In certain embodiments of any of formulas II, IIa or IIb, one of R⁵ andR⁶ and one of R³ and R⁴ together with the atoms to which they areattached form an imidazolinyl ring.

In certain embodiments of any of formulas II, IIa or IIb, m is 0 or 1,and n is 1.

In certain embodiments of any of formulas II, IIa or IIb, m is 0 or 1, nis 1, and R³ and R⁴ are hydrogen.

In certain embodiments of any of formulas II, IIa or IIb, m is 0 or 1, nis 1, R³ and R⁴ are hydrogen, one of R⁵ and R⁶ is hydrogen or alkyl, andthe other is: hydrogen; alkyl; amidinyl; aminocarbonyl; alkylcarbonyl;alkoxycarbonyl; aminocarbonylalkyl; aminoalkylcarbonyl;alkoxycarbonylalkyl; imidazolonyl; imidazolylcarbonyl; pyrrolylcarbonyl;pyrrolidinylcarbonyl; N-cyanoamidinyl; alkylsulfonyl;hydroxyalkylcarbonyl; aminosulfonyl; hydroxyalkyl; alkoxalkyl; oroptionally substituted heteroaryl.

In certain embodiments of any of formulas II, IIa or IIb, m is 0 or 1, nis 1, R³ and R⁴ are hydrogen, one of R⁵ and R⁶ is hydrogen and the otheris: hydrogen; alkyl; amidinyl; aminocarbonyl; alkylcarbonyl;alkoxycarbonyl; aminocarbonylalkyl; aminoalkylcarbonyl;alkoxycarbonylalkyl; alkylsulfonyl; or hydroxyalkylcarbonyl.

In certain embodiments of any of formulas II, IIa or IIb, m is 0 or 1, nis 1, R³ and R⁴ are hydrogen, one of R⁵ and R⁶ is hydrogen and the otheris alkyl.

In certain embodiments of any of formulas II, IIa or IIb, m is 0 or 1,and R² is: aminoalkyl; alkylaminoalkyl; dialkylaminoalkyl;imidazolinylaminoalkyl; imidazolinylalkyl, guanidinylalkyl;tetrahydropyrimidinylaminoalkyl; amidinylalkyl; urealkyl; amidinyl;heteroarylaminoalkyl; imidazolylaminoalkyl; guanidinylcarbonylalkyl;imidazolonylaminoalkyl; imidazolinylcarbonylaminoalkyl;aminocarbonylalkyl; pyrrolylcarbonylaminoalkyl;aminoalkylcarbonylaminoalkyl; alkoxycarbonylalkylaminoalkyl;N-cyanoguanidinylalkyl; alkylcarbonylaminoalkyl;aminocarbonylalkylaminoalkyl; pyrrolidinylcarbonylaminoalkyl;alkylsulfonamidoalkyl; aminosulfonamidoalkyl; alkoxycarbonylaminoalkyl;hydroxyalkylcarbonylaminoalkyl; hydroxyalkylaminoalkyl;alkoxyalkylaminoalkyl; or alkylsulfonylalkylaminoalkyl.

In certain embodiments of any of formulas II, IIa or IIb, m is 0 or 1,and R² is: aminoalkyl; alkylaminoalkyl; dialkylaminoalkyl;guanidinylalkyl; amidinylalkyl; urealkyl; amidinyl;guanidinylcarbonylalkyl; aminocarbonylalkyl;aminoalkylcarbonylaminoalkyl; alkylcarbonylaminoalkyl;aminocarbonylalkylaminoalkyl; or alkoxycarbonylaminoalkyl.

In certain embodiments of any of formulas II, IIa or IIb, m is 0 or 1,and R² is:

wherein R^(g) is hydrogen, alkyl, optionally substituted phenyl oroptionally substituted pyrimidinyl, R^(h), R^(i), R^(j) and R^(k) ineach independent occurrence is hydrogen or alkyl, and R^(m) is hydrogen,alkyl or —NR^(h)R^(i).

In certain embodiments of any of formulas II, IIa or IIb, m is 0 or 1,and R² is:

wherein R^(g), R^(h), R^(i) and R^(j) are hydrogen or alkyl.

In certain embodiments of any of formulas II, IIa or IIb, m is 0 or 1, nis 1, R³ and R⁴ are hydrogen, one of R⁵ and R⁶ is hydrogen or alkyl, andthe other is:

wherein R^(g) is hydrogen, alkyl, optionally substituted phenyl oroptionally substituted pyrimidinyl, R^(h), R^(i), R^(j) and R^(k) ineach independent occurrence is hydrogen or alkyl, and R^(m) is hydrogen,alkyl or —NR^(h)R^(i).

In certain embodiments of any of formulas II, IIa or IIb, m is 0 or 1, nis 1, R³ and R⁴ are hydrogen, one of R⁵ and R⁶ is hydrogen or alkyl, andthe other is:

wherein R^(g), R^(h), R^(i) and R^(j) are hydrogen or alkyl.

In certain embodiments of any of formulas II, IIa or IIb, m is 0 or 1, nis 1 or 2, and R³ and R⁴ together with the nitrogen to which they areattached form ═NR^(f) wherein R^(f) is hydrogen, and wherein R⁵ and R⁶are hydrogen.

In certain embodiments of any of formulas II, IIa or IIb, m is 0 or 1, nis 1 or 2, and R³ and R⁴ together with the nitrogen to which they areattached form ═O.

In certain embodiments of any of formulas II, IIa or IIb, m is 0 or 1,and n is 2.

In certain embodiments of any of formulas II, IIa or IIb, m is 0 or 1, nis 2, and R³ and R⁴ are hydrogen.

In certain embodiments of any of formulas II, IIa or IIb, m is 0 or 1, nis 2, R³ and R⁴ are hydrogen, one of R⁵ and R⁶ is hydrogen or alkyl, andthe other is: hydrogen; alkyl; amidinyl; aminocarbonyl; alkylcarbonyl;alkoxycarbonyl; aminocarbonylalkyl; aminoalkylcarbonyl;alkoxycarbonylalkyl; imidazolonyl; imidazolylcarbonyl; pyrrolylcarbonyl;pyrrolidinylcarbonyl; N-cyanoamidinyl; alkylsulfonyl;hydroxyalkylcarbonyl; aminosulfonyl; hydroxyalkyl; alkoxalkyl; oroptionally substituted heteroaryl.

In certain embodiments of any of formulas II, IIa or IIb, m is 0 or 1, nis 2, R³ and R⁴ are hydrogen, one of R⁵ and R⁶ is hydrogen and the otheris: hydrogen; alkyl; amidinyl; aminocarbonyl; alkylcarbonyl;alkoxycarbonyl; aminocarbonylalkyl; aminoalkylcarbonyl;alkoxycarbonylalkyl; alkylsulfonyl; or hydroxyalkylcarbonyl.

In certain embodiments of any of formulas II, IIa or IIb, m is 0 or 1, nis 2, R³ and R⁴ are hydrogen, one of R⁵ and R⁶ is hydrogen and the otheris alkyl.

In certain embodiments of any of formulas II, IIa or IIb, m is 0 or 1, nis 2, R³ and R⁴ are hydrogen, one of R⁵ and R⁶ is hydrogen or alkyl, andthe other is:

wherein R^(g) is hydrogen, alkyl, optionally substituted phenyl oroptionally substituted pyrimidinyl, R^(h), R^(i), R^(j) and R^(k) ineach independent occurrence is hydrogen or alkyl, and R^(m) is hydrogen,alkyl or —NR^(h)R^(i).

In certain embodiments of any of formulas II, IIa or IIb, m is 0 or 1, nis 2, R³ and R⁴ are hydrogen, one of R⁵ and R⁶ is hydrogen or alkyl, andthe other is:

wherein R^(g), R^(h), R^(i) and R^(j) are hydrogen or alkyl.

In certain embodiments of any of formulas II, IIa or IIb, m is 0 or 1,and n is 3.

In certain embodiments of any of formulas II, IIa or IIb, m is 0 or 1, nis 1, and R³ and R⁴ are hydrogen.

In certain embodiments of any of formulas II, IIa or IIb, p is 2, q is2, m is 0 or 1, n is 3, R³ and R⁴ are hydrogen, one of R⁵ and R⁶ ishydrogen or alkyl, and the other is: hydrogen; alkyl; amidinyl;aminocarbonyl; alkylcarbonyl; alkoxycarbonyl; aminocarbonylalkyl;aminoalkylcarbonyl; alkoxycarbonylalkyl; imidazolonyl;imidazolylcarbonyl; pyrrolylcarbonyl; pyrrolidinylcarbonyl;N-cyanoamidinyl; alkylsulfonyl; hydroxyalkylcarbonyl; aminosulfonyl;hydroxyalkyl; alkoxalkyl; or optionally substituted heteroaryl.

In certain embodiments of any of formulas II, IIa or IIb, p is 2, q is2, m is 0 or 1, n is 3, R³ and R⁴ are hydrogen, one of R⁵ and R⁶ ishydrogen and the other is: hydrogen; alkyl; amidinyl; aminocarbonyl;alkylcarbonyl; alkoxycarbonyl; aminocarbonylalkyl; aminoalkylcarbonyl;alkoxycarbonylalkyl; alkylsulfonyl; or hydroxyalkylcarbonyl.

In certain embodiments of any of formulas II, IIa or IIb, p is 2, q is2, m is 0 or 1, n is 3, R³ and R⁴ are hydrogen, one of R⁵ and R⁶ ishydrogen or alkyl, and the other is:

wherein R^(g) is hydrogen, alkyl, optionally substituted phenyl oroptionally substituted pyrimidinyl, R^(h), R^(i), R^(j) and R^(k) ineach independent occurrence is hydrogen or alkyl, and R^(m) is hydrogen,alkyl or —NR^(h)R^(i).

In certain embodiments of any of formulas II, IIa or IIb, p is 2, q is2, m is 0 or 1, n is 3, R³ and R⁴ are hydrogen, one of R⁵ and R⁶ ishydrogen or alkyl, and the other is:

wherein R^(g), R^(h), R^(i) and R^(j) are hydrogen or alkyl.

In certain embodiments of the invention, the subject compounds may be ofthe formula IIIa:

wherein:

s is from 0 to 4;

each R⁷ is independently halo, alkyl, alkoxy, haloalkyl, heteroalkyl,cyano, —S(O)_(r)R^(a), —C(═O)—NR^(b)R^(c), —SO₂—NR^(b)R^(c),—N(R^(d))—C(═O)—R^(e), or —C(═O)—R^(e), where r is from 0 to 2, R^(a),R^(b), R^(c) and R^(d) each independently is hydrogen or alkyl, andR^(e) is hydrogen, alkyl, alkoxy or hydroxy; and

m, n, R¹, R³, R⁴, R⁵ and R⁶ are as defined herein.

In certain embodiments of the invention, the subject compounds may be ofthe formula IIIb:

wherein:

s is from 0 to 4;

each R⁷ is independently halo, alkyl, alkoxy, haloalkyl, heteroalkyl,cyano, —S(O)_(r)R^(a), —C(═O)—NR^(b)R^(c), —SO₂—NR^(b)R^(c),—N(R^(d))—C(═O)—R^(e), or —C(═O)—R^(e), where r is from 0 to 2, R^(a),R^(b), R^(c) and R^(d) each independently is hydrogen or alkyl, andR^(e) is hydrogen, alkyl, alkoxy or hydroxy; and

m, n, R¹, R³, R⁴, R⁵ and R⁶ are as defined herein.

In certain embodiments of the invention, the subject compounds may be ofthe formula IIIc:

wherein:

s is from 0 to 4;

each R⁷ is independently halo, alkyl, alkoxy, hydroxy, haloalkyl,heteroalkyl, cyano, —S(O)_(r)R^(a), —C(═O)—NR^(b)R^(c),—SO₂—NR^(b)R^(c), —N(R^(d))—C(═O)—R^(e), or —C(═O)—R^(e), where r isfrom 0 to 2, R^(a), R^(b), R^(c) and R^(d) each independently ishydrogen or alkyl, and R^(e) is hydrogen, alkyl, alkoxy or hydroxy; and

m, n, R¹, R³, R⁴, R⁵ and R⁶ are as defined herein.

In certain embodiments of the invention, the subject compounds may be ofthe formula IIId:

wherein:

s is from 0 to 4;

each R⁷ is independently halo, alkyl, alkoxy, hydroxy, haloalkyl,heteroalkyl, cyano, —S(O)_(r)R^(a), —C(═O)—NR^(b)R^(c),—SO₂—NR^(b)R^(c), —N(R^(d))—C(═O)—R^(e), or —C(═O)—R^(e), where r isfrom 0 to 2, R^(a), R^(b), R^(c) and R^(d) each independently ishydrogen or alkyl, and R^(e) is hydrogen, alkyl, alkoxy or hydroxy; and

m, n, R¹, R³, R⁴, R⁵ and R⁶ are as defined herein.

In many embodiments of any of formulas IIIa, IIIb, IIIc or IIId, m is 0or 1.

In certain embodiments of any of formulas IIIa, IIIb, IIIc or IIId, R¹is halo.

In certain embodiments of any of formulas IIIa, IIIb, IIIc or IIId, m is0 or 1 and R¹ is located at the 8-position of the tetralin ring system.

In certain embodiments of any of formulas IIIa, IIIb, IIIc or IIId, n is1.

In certain embodiments of any of formulas IIIa, IIIb, IIIc or IIId, n is2.

In certain embodiments of any of formulas IIIa, IIIb, IIIc or IIId, n is3.

In certain embodiments of any of formulas IIIa, IIIb, IIIc or IIId, R³and R⁴ are hydrogen.

In certain embodiments of any of formulas IIIa, IIIb, IIIc or IIId, oneof R⁵ and R⁶ is hydrogen and the other is alkyl.

In certain embodiments of any of formulas IIIa, IIIb, IIIc or IIId, R⁵and R⁶ are hydrogen.

In certain embodiments of any of formulas IIIa, IIIb, IIIc or IIId, oneof R⁵ and R⁶ is hydrogen or alkyl and the other is: hydrogen; alkyl;amidinyl; aminocarbonyl; alkylcarbonyl; alkoxycarbonyl;aminocarbonylalkyl; aminoalkylcarbonyl; alkoxycarbonylalkyl;imidazolonyl; imidazolylcarbonyl; pyrrolylcarbonyl;pyrrolidinylcarbonyl; N-cyanoamidinyl; alkylsulfonyl;hydroxyalkylcarbonyl; aminosulfonyl; hydroxyalkyl; or alkoxalkyl.

In certain embodiments of any of formulas IIIa, IIIb, IIIc or IIId, oneof R⁵ and R⁶ is hydrogen or alkyl and the other is: hydrogen; alkyl;amidinyl; aminocarbonyl; alkylcarbonyl; alkoxycarbonyl;aminocarbonylalkyl; aminoalkylcarbonyl; alkoxycarbonylalkyl;imidazolonyl; imidazolylcarbonyl; pyrrolylcarbonyl;pyrrolidinylcarbonyl; N-cyanoamidinyl; alkylsulfonyl;hydroxyalkylcarbonyl; aminosulfonyl; hydroxyalkyl; alkoxalkyl; oroptionally substituted heteroaryl.

In certain embodiments of any of formulas IIIa, IIIb, IIIc or IIId, oneof R⁵ and R⁶ is hydrogen and the other is: hydrogen; alkyl; amidinyl;aminocarbonyl; alkylcarbonyl; alkoxycarbonyl; aminocarbonylalkyl;aminoalkylcarbonyl; alkoxycarbonylalkyl; alkylsulfonyl; orhydroxyalkylcarbonyl.

In certain embodiments of any of formulas IIIa, IIIb, IIIc or IIId, oneof R⁵ and R⁶ is hydrogen and the other is heteroaryl selected frombenzothiazolyl, indolyl, thienyl, furanyl, pyridinyl, pyrimdinyl,pyrrolyl, pyrazolyl and imidazolyl, each optionally substituted.

In certain embodiments of any of formulas IIIa, IIIb, IIIc or IIId, oneof R⁵ and R⁶ is hydrogen and the other is heteroaryl selected frompyrimidinyl, benzothiazol-2-yl, and5,5-dimethyl-1,4,5,6-tetrahydropyrimidinyl.

In certain embodiments of any of formulas IIIa, IIIb, IIIc or IIId, R⁵and R⁶ together with the nitrogen to which they are attached form anamidinyl group.

In certain embodiments of any of formulas IIIa, IIIb, IIIc or IIId, R⁵and R⁶ together with the nitrogen to which they are attached form aguanidinyl group.

In certain embodiments of any of formulas IIIa, IIIb, IIIc or IIId, R⁵and R⁶ together with the nitrogen to which they are attached form a ureagroup.

In certain embodiments of any of formulas IIIa, IIIb, IIIc or IIId, R³and R⁴ together with the nitrogen to which they are attached form═NR^(f) wherein R^(f) is hydrogen.

In certain embodiments of any of formulas IIIa, IIIb, IIIc or IIId, R³and R⁴ together with the nitrogen to which they are attached form ═O.

In certain embodiments of any of formulas IIIa, IIIb, IIIc or IIId, oneof R⁵ and R⁶ and one of R³ and R⁴ together with the atoms to which theyare attached form an imidazolinyl ring.

In certain embodiments of either of formula IIIa or IIIb, R⁵ and R⁶together with the nitrogen to which they are attached form or a five- orsix-membered heteroaryl ring that is optionally substituted and whichoptionally includes an additional nitrogen heteroatom.

In certain embodiments of any of formulas IIIa, IIIb, IIIc or IIId, R⁵and R⁶ together with the nitrogen to which they are attached form or afive- or six-membered heteroaryl ring selected from pyridinyl,pyrimidinyl, pyrrolyl, imidazolyl or pyrazolyl, each optionallysubstituted.

In certain embodiments of any of formulas IIIa, IIIb, IIIc or IIId, R⁵and R⁶ together with the nitrogen to which they are attached form theyare attached form or a five- or six-membered heterocyclic ring that isoptionally substituted and which optionally includes an additionalheteroatom selected from O, N and S.

In certain embodiments of any of formulas IIIa, IIIb, IIIc or IIId, R⁵and R⁶ together with the nitrogen to which they are attached form theyare attached form or a five- or six-membered heterocyclic ring selectedfrom pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azepinyl anddiazepinyl.

In certain embodiments of either of formula IIIa or IIIb, one of R⁵ andR⁶ and one of R³ and R⁴ together with the atoms to which they areattached form an imidazolinyl ring.

In certain embodiments of either of formula IIIa or IIIb, s is from 0 to2 and R⁷ is halo, alkyl, alkoxy, haloalkyl, hydroxy, cyano ormethanesulfonyl.

In certain embodiments of either of formula IIIa or IIIb, s is 0 or 1and R⁷ is halo.

In certain embodiments of any of formulas IIIa, IIIb, IIIc or IIId, m is0 or 1, and n is 1.

In certain embodiments of any of formulas IIIa, IIIb, IIIc or IIId, m is0 or 1, n is 1, and R³ and R⁴ are hydrogen.

In certain embodiments of any of formulas IIIa, IIIb, IIIc or IIId, m is0 or 1, n is 1, R³ and R⁴ are hydrogen, one of R⁵ and R⁶ is hydrogen oralkyl, and the other is: hydrogen; alkyl; amidinyl; aminocarbonyl;alkylcarbonyl; alkoxycarbonyl; aminocarbonylalkyl; aminoalkylcarbonyl;alkoxycarbonylalkyl; imidazolonyl; imidazolylcarbonyl; pyrrolylcarbonyl;pyrrolidinylcarbonyl; N-cyanoamidinyl; alkylsulfonyl;hydroxyalkylcarbonyl; aminosulfonyl; hydroxyalkyl; alkoxalkyl; oroptionally substituted heteroaryl.

In certain embodiments of any of formulas IIIc, IIIb, IIIc or IIId, m is0 or 1, n is 1, R³ and R⁴ are hydrogen, one of R⁵ and R⁶ is hydrogen andthe other is: hydrogen; alkyl; amidinyl; aminocarbonyl; alkylcarbonyl;alkoxycarbonyl; aminocarbonylalkyl; aminoalkylcarbonyl;alkoxycarbonylalkyl; alkylsulfonyl; or hydroxyalkylcarbonyl.

In certain embodiments of any of formulas IIIa, IIIb, IIIc or IIId, m is0 or 1, n is 1, R³ and R⁴ are hydrogen, one of R⁵ and R⁶ is hydrogen andthe other is alkyl.

In certain embodiments of any of formulas IIIa, IIIb, IIIc or IIId, m is0 of 1, n is 1, R³ and R⁴ are hydrogen, one of R⁵ and R⁶ is hydrogen oralkyl, and the other is:

wherein R^(g) is hydrogen, alkyl, optionally substituted phenyl oroptionally substituted pyrimidinyl, R^(h), R^(i), R^(j) and R^(k) ineach independent occurrence is hydrogen or alkyl, and R^(m) is hydrogen,alkyl or —NR^(h)R^(i).

In certain embodiments of any of formulas IIIa, IIIb, IIIc or IIId, m is0 or 1, n is 1, R³ and R⁴ are hydrogen, one of R⁵ and R⁶ is hydrogen oralkyl, and the other is:

wherein R^(g), R^(h), R^(i) and R^(j) are hydrogen or alkyl.

In certain embodiments of any of formulas IIIa, IIIb, IIIc or IIId, m is0 or 1, n is 1 or 2, and R³ and R⁴ together with the nitrogen to whichthey are attached form ═NR^(f) wherein R^(f) is hydrogen, and wherein R⁵and R⁶ are hydrogen.

In certain embodiments of any of formulas IIIa, IIIb, IIIc or IIId, m is0 or 1, n is 1 or 2, and R³ and R⁴ together with the nitrogen to whichthey are attached form ═O.

In certain embodiments of any of formulas IIIa, IIIb, IIIc or IIId, m is0 or 1, and n is 2.

In certain embodiments of any of formulas IIIa, IIIb, IIIc or IIId, m is0 or 1, n is 2, and R³ and R⁴ are hydrogen.

In certain embodiments of either of formula IIIa or IIIb, m is 0 or 1, nis 2, R³ and R⁴ are hydrogen, one of R⁵ and R⁶ is hydrogen or alkyl, andthe other is: hydrogen; alkyl; amidinyl; aminocarbonyl; alkylcarbonyl;alkoxycarbonyl; aminocarbonylalkyl; aminoalkylcarbonyl;alkoxycarbonylalkyl; imidazolonyl; imidazolylcarbonyl; pyrrolylcarbonyl;pyrrolidinylcarbonyl; N-cyanoamidinyl; alkylsulfonyl;hydroxyalkylcarbonyl; aminosulfonyl; hydroxyalkyl; alkoxalkyl; oroptionally substituted heteroaryl.

In certain embodiments of any of formulas IIIa, IIIb, IIIc or IIId, m is0 or 1, n is 2, R³ and R⁴ are hydrogen, one of R⁵ and R⁶ is hydrogen andthe other is: hydrogen; alkyl; amidinyl; aminocarbonyl; alkylcarbonyl;alkoxycarbonyl; aminocarbonylalkyl; aminoalkylcarbonyl;alkoxycarbonylalkyl; alkylsulfonyl; or hydroxyalkylcarbonyl.

In certain embodiments of any of formulas IIIa, IIIb, IIIc or IIId, m is0 or 1, n is 2, R³ and R⁴ are hydrogen, one of R⁵ and R⁶ is hydrogen andthe other is alkyl.

In certain embodiments of any of formulas IIIa, IIIb, IIIc or IIId, m is0 or 1, n is 2, R³ and R⁴ are hydrogen, one of R⁵ and R⁶ is hydrogen oralkyl, and the other is:

wherein R^(g) is hydrogen, alkyl, optionally substituted phenyl oroptionally substituted pyrimidinyl, R^(h), R^(i), R^(j) and R^(k) ineach independent occurrence is hydrogen or alkyl, and R^(m) is hydrogen,alkyl or —NR^(h)R^(i).

In certain embodiments of any of formulas IIIa, IIIb, IIIc or IIId, m is0 or 1, n is 2, R³ and R⁴ are hydrogen, one of R⁵ and R⁶ is hydrogen oralkyl, and the other is:

wherein R^(g), R^(h), R^(i) and R^(j) are hydrogen or alkyl.

In certain embodiments of any of formulas IIIa, IIIb, IIIc or IIId, m is0 or 1, and n is 3.

In certain embodiments of any of formulas IIIa, IIIb, IIIc or IIId, m is0 or 1, n is 1, and R³ and R⁴ are hydrogen.

In certain embodiments of any of formulas IIIa, IIIb, IIIc or IIId, p is2, q is 2, m is 0 or 1, n is 3, R³ and R⁴ are hydrogen, one of R⁵ and R⁶is hydrogen or alkyl, and the other is: hydrogen; alkyl; amidinyl;aminocarbonyl; alkylcarbonyl; alkoxycarbdnyl; aminocarbonylalkyl;aminoalkylcarbonyl; alkoxycarbonylalkyl; imidazolonyl;imidazolylcarbonyl; pyrrolylcarbonyl; pyrrolidinylcarbonyl;N-cyanoamidinyl; alkylsulfonyl; hydroxyalkylcarbonyl; aminosulfonyl;hydroxyalkyl; alkoxalkyl; or optionally substituted heteroaryl.

In certain embodiments of any of formulas IIIa, IIIb, IIIc or IIId, p is2, q is 2, m is 0 or 1, n is 3, R³ and R⁴ are hydrogen, one of R⁵ and R⁶is hydrogen and the other is: hydrogen; alkyl; amidinyl; aminocarbonyl;alkylcarbonyl; alkoxycarbonyl; aminocarbonylalkyl; aminoalkylcarbonyl;alkoxycarbonylalkyl; alkylsulfonyl; or hydroxyalkylcarbonyl.

In certain embodiments of any of formulas IIIa, IIIb, IIIc or IIId, p is2, q is 2, m is 0 or 1, n is 3, R³ and R⁴ are hydrogen, one of R⁵ and R⁶is hydrogen or alkyl, and the other is:

wherein R^(g) is hydrogen, alkyl, optionally substituted phenyl oroptionally substituted pyrimidinyl, R^(h), R^(i), R^(j) and R^(k) ineach independent occurrence is hydrogen or alkyl, and R^(m) is hydrogen,alkyl or —NR^(h)R^(i).

In certain embodiments of any of formulas IIIa, IIIb, IIIc or IIId, p is2, q is 2, m is 0 or 1, n is 3, R³ and R⁴ are hydrogen, one of R⁵ and R⁶is hydrogen or alkyl, and the other is:

wherein R^(g), R^(h), R^(i) and R^(j) are hydrogen or alkyl.

The subject compounds may, in certain embodiments, be more specificallyof formula IVa:

wherein m, n, s, R¹, R⁵, R⁶ and R⁷ are as defined herein.

The subject compounds may, in certain embodiments, be more specificallyof formula IVb:

wherein m, n, s, R¹, R⁵, R⁶ and R⁷ are as defined herein.

In many embodiments of either of formula IVa or formula IVb, m is 0 or1.

In certain embodiments of either of formula IVa or formula IVb, R¹ ishalo.

In certain embodiments of either of formula IVa or formula IVb, m is 0or 1 and R¹ is located at the 8-position of the tetralin ring system.

In certain embodiments of either of formula IVa or formula IVb, n is 1.

In certain embodiments of either of formula IVa or formula IVb, n is 2.

In certain embodiments of either of formula IVa or formula IVb, n is 3.

In certain embodiments of either of formula IVa or formula IVb, one ofR⁵ and R⁶ is hydrogen and the other is alkyl.

In certain embodiments of either of formula IVa or formula IVb, R⁵ andR⁶ are hydrogen.

In certain embodiments of either of formula IVa or formula IVb, one ofR⁵ and R⁶ is hydrogen or alkyl and the other is: hydrogen; alkyl;amidinyl; aminocarbonyl; alkylcarbonyl; alkoxycarbonyl;aminocarbonylalkyl; aminoalkylcarbonyl; alkoxycarbonylalkyl;imidazolonyl; imidazolylcarbonyl; pyrrolylcarbonyl;pyrrolidinylcarbonyl; N-cyanoamidinyl; alkylsulfonyl;hydroxyalkylcarbonyl; aminosulfonyl; hydroxyalkyl; or alkoxalkyl.

In certain embodiments of either of formula IVa or formula IVb, one ofR⁵ and R⁶ is hydrogen or alkyl and the other is: hydrogen; alkyl;amidinyl; aminocarbonyl; alkylcarbonyl; alkoxycarbonyl;aminocarbonylalkyl; aminoalkylcarbonyl; alkoxycarbonylalkyl;imidazolonyl; imidazolylcarbonyl; pyrrolylcarbonyl;pyrrolidinylcarbonyl; N-cyanoamidinyl; alkylsulfonyl;hydroxyalkylcarbonyl; aminosulfonyl; hydroxyalkyl; alkoxalkyl; oroptionally substituted heteroaryl.

In certain embodiments of either of formula IVa or formula IVb, one ofR⁵ and R⁶ is hydrogen and the other is: hydrogen; alkyl; amidinyl;aminocarbonyl; alkylcarbonyl; alkoxycarbonyl; aminocarbonylalkyl;aminoalkylcarbonyl; alkoxycarbonylalkyl; alkylsulfonyl; orhydroxyalkylcarbonyl.

In certain embodiments of either of formula IVa or formula IVb, one ofR⁵ and R⁶ is hydrogen and the other is heteroaryl selected frombenzothiazolyl, indolyl, thienyl, furanyl, pyridinyl, pyrimdinyl,pyrrolyl, pyrazolyl and imidazolyl, each optionally substituted.

In certain embodiments of either of formula IVa or formula IVb, one ofR⁵ and R⁶ is hydrogen and the other is heteroaryl selected frompyrimidinyl, benzothiazol-2-yl, and5,5-dimethyl-1,4,5,6-tetrahydropyrimidinyl.

In certain embodiments of either of formula IVa or formula IVb, R⁵ andR⁶ together with the nitrogen to which they are attached form anamidinyl group.

In certain embodiments of either of formula IVa or formula IVb, R⁵ andR⁶ together with the nitrogen to which they are attached form aguanidinyl group.

In certain embodiments of either of formula IVa or formula IVb, R⁵ andR⁶ together with the nitrogen to which they are attached form a ureagroup.

In certain embodiments of either of formula IVa or formula IVb, R⁵ andR⁶ together with the nitrogen to which they are attached form or a five-or six-membered heteroaryl ring that is optionally substituted and whichoptionally includes an additional nitrogen heteroatom.

In certain embodiments of either of formula IVa or formula IVb, R⁵ andR⁶ together with the nitrogen to which they are attached form or a five-or six-membered heteroaryl ring selected from pyridinyl, pyrimidinyl,pyrrolyl, imidazolyl or pyrazolyl, each optionally substituted.

In certain embodiments of either of formula IVa or formula IVb, R⁵ andR⁶ together with the nitrogen to which they are attached form they areattached form or a five- or six-membered heterocyclic ring that isoptionally substituted and which optionally includes an additionalheteroatom selected from O, N and S.

In certain embodiments of either of formula IVa or formula IVb, R⁵ andR⁶ together with the nitrogen to which they are attached form they areattached form or a five- or six-membered heterocyclic ring selected frompyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azepinyl anddiazepinyl.

In certain embodiments of either of formula IVa or formula IVb, one ofR⁵ and R⁶ and one of R³ and R⁴ together with the atoms to which they areattached form an imidazolinyl ring.

In certain embodiments of either of formula IVa or, formula IVb, s isfrom 0 to 2 and R⁷ is halo, alkyl, alkoxy, haloalkyl, hydroxy, cyano ormethanesulfonyl.

In certain embodiments of either of formula IVa or formula IVb, s is 0or 1 and R⁷ is halo.

In certain embodiments of either of formula IVa or formula IVb, m is 0or 1, and n is 1.

In certain embodiments of either of formula IVa or formula IVb, m is 0or 1, n is 1, one of R⁵ and R⁶ is hydrogen or alkyl, and the other is:hydrogen; alkyl; amidinyl; aminocarbonyl; alkylcarbonyl; alkoxycarbonyl;aminocarbonylalkyl; aminoalkylcarbonyl; alkoxycarbonylalkyl;imidazolonyl; imidazolylcarbonyl; pyrrolylcarbonyl;pyrrolidinylcarbonyl; N-cyanoamidinyl; alkylsulfonyl;hydroxyalkylcarbonyl; aminosulfonyl; hydroxyalkyl; alkoxalkyl; oroptionally substituted heteroaryl.

In certain embodiments of either of formula IVa or formula IVb, m is 0or 1, n is 1, one of R⁵ and R⁶ is hydrogen and the other is: hydrogen;alkyl; amidinyl; aminocarbonyl; alkylcarbonyl; alkoxycarbonyl;aminocarbonylalkyl; aminoalkylcarbonyl; alkoxycarbonylalkyl;alkylsulfonyl; or hydroxyalkylcarbonyl.

In certain embodiments of either of formula IVa or formula IVb, m is 0or 1, n is 1, one of R⁵ and R⁶ is hydrogen and the other is alkyl.

In certain embodiments of either of formula IVa or formula IVb, m is 0or 1, n is 1, one of R⁵ and R⁶ is hydrogen or alkyl, and the other is:

wherein R^(g) is hydrogen, alkyl, optionally substituted phenyl oroptionally substituted pyrimidinyl, R^(h), R^(i), R^(j) and R^(k) ineach independent occurrence is hydrogen or alkyl, and R^(m) is hydrogen,alkyl or —NR^(h)R^(i).

In certain embodiments of either of formula IVa or formula IVb, m is 0or 1, n is 1, R³ and R⁴ are hydrogen, one of R⁵ and R⁶ is hydrogen oralkyl, and the other is:

wherein R⁸, R^(h), R^(i) and R^(j) are hydrogen or alkyl.

In certain embodiments of either of formula IVa or formula IVb, m is 0or 1, and n is 2.

In certain embodiments of either of formula IIIa or IIIb, m is 0 or 1, nis 2, one of R⁵ and R⁶ is hydrogen or alkyl, and the other is: hydrogen;alkyl; amidinyl; aminocarbonyl; alkylcarbonyl; alkoxycarbonyl;aminocarbonylalkyl; aminoalkylcarbonyl; alkoxycarbonylalkyl;imidazolonyl; imidazolylcarbonyl; pyrrolylcarbonyl;pyrrolidinylcarbonyl; N-cyanoamidinyl; alkylsulfonyl;hydroxyalkylcarbonyl; aminosulfonyl; hydroxyalkyl; alkoxalkyl; oroptionally substituted heteroaryl.

In certain embodiments of either of formula IVa or formula IVb, m is 0or 1, n is 2, one of R⁵ and R⁶ is hydrogen and the other is: hydrogen;alkyl; amidinyl; aminocarbonyl; alkylcarbonyl; alkoxycarbonyl;aminocarbonylalkyl; aminoalkylcarbonyl; alkoxycarbonylalkyl;alkylsulfonyl; or hydroxyalkylcarbonyl.

In certain embodiments of either of formula IVa or formula IVb, m is 0or 1, n is 2, one of R⁵ and R⁶ is hydrogen and the other is alkyl.

In certain embodiments of either of formula IVa or formula IVb, m is 0or 1, n is 2, one of R⁵ and R⁶ is hydrogen or alkyl, and the other is:

wherein R^(g) is hydrogen, alkyl, optionally substituted phenyl oroptionally substituted pyrimidinyl, R^(h), R^(i), R^(j) and R^(k) ineach independent occurrence is hydrogen or alkyl, and R^(m) is hydrogen,alkyl or —NR^(h)R^(i).

In certain embodiments of either of formula IVa or formula IVb, m is 0or 1, n is 2, one of R⁵ and R⁶ is hydrogen or alkyl, and the other is:

wherein R^(g), R^(h), R^(i) and R^(j) are hydrogen or alkyl.

In certain embodiments of either of formula IVa or formula IVb, m is 0or 1, and n is 3.

In certain embodiments of either of formula IVa or formula IVb, p is 2,q is 2, m is 0 or 1, n is 3, one of R⁵ and R⁶ is hydrogen or alkyl, andthe other is: hydrogen; alkyl; amidinyl; aminocarbonyl; alkylcarbonyl;alkoxycarbonyl; aminocarbonylalkyl; aminoalkylcarbonyl;alkoxycarbonylalkyl; imidazolonyl; imidazolylcarbonyl; pyrrolylcarbonyl;pyrrolidinylcarbonyl; N-cyanoamidinyl; alkylsulfonyl;hydroxyalkylcarbonyl; aminosulfonyl; hydroxyalkyl; alkoxalkyl; oroptionally substituted heteroaryl.

In certain embodiments of either of formula IVa or formula IVb, p is 2,q is 2, m is 0 or 1, n is 3, one of R⁵ and R⁶ is hydrogen and the otheris: hydrogen; alkyl; amidinyl; aminocarbonyl; alkylcarbonyl;alkoxycarbonyl; aminocarbonylalkyl; aminoalkylcarbonyl;alkoxycarbonylalkyl; alkylsulfonyl; or hydroxyalkylcarbonyl.

In certain embodiments of either of formula IVa or formula IVb, p is 2,q is 2, m is 0 or 1, n is 3, one of R⁵ and R⁶ is hydrogen or alkyl, andthe other is:

wherein R^(g) is hydrogen, alkyl, optionally substituted phenyl oroptionally substituted pyrimidinyl, R^(h), R^(i), R^(j) and R^(k) ineach independent occurrence is hydrogen or alkyl, and R^(m) is hydrogen,alkyl or —NR^(h)R^(i).

In certain embodiments of either of formula IVa or formula IVb, p is 2,q is 2, m is 0 or 1, n is 3, one of R⁵ and R⁶ is hydrogen or alkyl, andthe other is:

wherein R^(g), R^(h), R^(i) and R^(j) are hydrogen or alkyl.

In certain embodiments of formula IVa m is 0 or 1, n is 1, s is 0 or 1,and R⁵ and R⁶ are hydrogen. In such embodiments R¹ and R⁷ are preferablyhalo.

In certain embodiments of formula IVa m is 0 or 1, n is 1, s is 0 or 1,one of R⁵ and R⁶ is hydrogen, and the other is alkyl, preferably methyl.In such embodiments R¹ and R⁷ are preferably halo.

In certain embodiments of formula IVa m is 0 or 1, n is 1, s is 0 or 1,one of R⁵ and R⁶ is hydrogen, and the other is amidinyl. In suchembodiments R¹ and R⁷ are preferably halo.

In certain embodiments of formula IVa m is 0 or 1, n is 1, s is 0 or 1,one of R⁵ and R⁶ is hydrogen, and the other is aminocarbonyl. In suchembodiments R¹ and R⁷ are preferably halo.

In certain embodiments of formula IVa m is 0 or 1, n is 1, s is 0 or 1,one of R⁵ and R⁶ is hydrogen, and the other is alkylcarbonyl. In suchembodiments R¹ and R⁷ are preferably halo.

Iri certain embodiments of formula IVa m is 0 or 1, n is 1, s is 0 or 1,one of R⁵ and R⁶ is hydrogen, and the other is alkoxycarbonyl. In suchembodiments R¹ and R⁷ are preferably halo.

In certain embodiments of formula IVa m is 0 or 1, n is 1, s is 0 or 1,one of R⁵ and R⁶ is hydrogen, and the other is aminocarbonylalkyl. Insuch embodiments R¹ and R⁷ are preferably halo.

In certain embodiments of formula IVa m is 0 or 1, n is 1, s is 0 or 1,one of R⁵ and R⁶ is hydrogen, and the other is alkoxycarbonylalkyl. Insuch embodiments R¹ and R⁷ are preferably halo.

In certain embodiments of formula IVa m is 0 or 1, n is 1, s is 0 or 1,one of R⁵ and R⁶ is hydrogen, and the other is alkylsulfonyl. In suchembodiments R¹ and R⁷ are preferably halo.

In certain embodiments of formula IVa m is 0 or 1, n is 1, s is 0 or 1,one of R⁵ and R⁶ is hydrogen, and the other is hydroxyalkylcarbonyl. Insuch embodiments R¹ and R⁷ are preferably halo.

Where any of R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R^(a), R^(b), R^(c), R^(d),R^(e), R^(f), R^(g), R^(h), R^(i), R^(j), R^(k) and R^(m) herein arealkyl or contain an alkyl moiety, such alkyl is preferably lower alkyl,i.e. C₁-C₆alkyl, and more preferably C₁-C₄alkyl.

Representative compounds in accordance with the invention are shown inTable 1 together with melting point or mass spectrum M+H associated witheach compound. Melting points in many instances are shown forcorresponding addition salts.

TABLE 1 Mp or # Structure Name M + H 1

2-(5-Benzenesulfonyl-indan-1-yl)- ethylamine 302 2

[2-(5-Benzenesulfonyl-indan-1-yl)-ethyl]-(4,5-dihydro-1H-imidazol-2-yl)- amine 370 3

1-[2-(5-Benzenesulfonyl-indan-1-yl)- ethyl]-1-methyl-1H-pyrrolium iodide367 4

[2-(5-Benzenesulfonyl-indan-1-yl)- ethyl]-methyl-amine 316 5

3-(5-Benzenesulfonyl-indan-1-yl)- propylamine 316 6

2-[2-(5-Benzenesulfonyl-indan-l-yl)- ethyl]-4,5-dihydro-1H-imidazole 3557

C-(7-Benzenesulfonyl-1,2,3,4- tetrahydro-naphthalen-1-yl)- methylamine302 8

(7-Benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl)-benzothiazol-2- yl-amine 435 9

N-[2-(7-Benzenesulfonyl-1,2,3,4- tetrahydro-naphthalen-1-yl)-ethyl]-guanidine 358 10

C-[7-(4-Fluoro-benzenesulfonyl)- 1,2,3,4-tetrahydro-naphthalen-1-yl]-methylamine 11

(7-Benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl)-(5,5-dimethyl-1,4,5,6-tetrahydro-pyrimidin-2-yl)- amine 320 12

2-(7-Benzenesulfonyl-1,2,3,4- tetrahydro-naphthalen-1-yl)-acetamidine329 13

2-(7-Benzenesulfonyl-1,2,3,4- tetrahydro-naphthalen-1-yl)-ethylamine 31614

(6-Benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl)-(4,5-dihydro- 1H-imidazol-2-yl)-amine 370 15

N-(7-Benzenesulfonyl-1,2,3,4- tetrahydro-naphthalen-1-ylmethyl)-N′-methyl-N″-phenyl-guanidine 434 16

N-(6-Benzenesulfonyl-1,2,3,4- tetrahydro-naphthalen-1-ylmethyl)-guanidine 344 17

N-(7-Benzenesulfonyl-1,2,3,4- tetrahydro-naphthalen-1-ylmethyl)-guanidine 344 18

1-[2-(7-Benzenesulfonyl-1,2,3,4- tetrahydro-naphthalen-1-yl)-ethyl]-1H-imidazole 367 19

[2-(7-Benzenesulfonyl-1,2,3,4- tetrahydro-naphthalen-1-yl)-ethyl]-pyrimidin-2-yl-amine 394 20

N′-[2-(7-Benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-ethyl]-N,N- dimethyl-acetamidine 385 21

3-(6-Benzenesulfonyl-1,2,3,4- tetrahydro-naphthalen-1-yl)-propionamidine 343 22

[2-(6-Benzenesulfonyl-1,2,3,4- tetrahydro-naphthalen-1-yl)-ethyl]-dimethyl-amine 344 23

C-(6-Benzenesulfonyl-1,2,3,4- tetrahydro-naphthalen-1-yl)- methylamine302 24

C-[6-(3-Chloro-benzenesulfonyl)- 1,2,3,4-tetrahydro-naphthalen-1-yl]-methylamine 336 25

(6-Benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl)-methyl-amine 316 26

(6-Benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl)-pyrimidin-2-yl- amine 380 27

N-(6-Benzenesulfonyl-1,2,3,4- tetrahydro-naphthalen-1-ylmethyl)-acetamidine 343 28

2-(6-Benzenesulfonyl-1,2,3,4- tetrahydro-naphthalen-1-yl)-ethylamine 31629

2-[6-(2-Fluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-ethylamine 334 30

3-(6-Benzenesulfonyl-1,2,3,4- tetrahydro-naphthalen-1-yl)- propylamine330 31

[6-(3-Chloro-benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]- methyl-amine 350 32

C-[6-(2-Fluoro-benzenesulfonyl)- 1,2,3,4-tetrahydro-naphthalen-1-yl]-methylamine 320 33

1-[2-(6-Benzenesulfonyl-1,2,3,4- tetrahydro-naphthalen-1-yl)-ethyl]-1H-imidazole 367 34

3-[6-(3-Fluoro-benzenesulfonyl)-1,2,3,4- tetrahydro-naphthalen-1-yl]-propylamine 348 35

C-(6-Benzenesulfonyl-7-methoxy- 1,2,3,4-tetrahydro-naphthalen-1-yl)-methylamine 332 36

(6-Benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl)-dimethyl-amine 330 37

(6-Benzenesulfonyl-7-methoxy-1,2,3,4- tetrahydro-naphthalen-1-ylmethyl)-methyl-amine 346 38

[2-(6-Benzenesulfonyl-1,2,3,4- tetrahydro-naphthalen-1-yl)-ethyl]-dimethyl-amine 344 39

(R)-(6-Benzenesulfonyl-1,2,3,4- tetrahydro-naphthalen-1-ylmethyl)-methyl-amine 316 40

(S)-(6-Benzenesulfonyl-1,2,3,4- tetrahydro-naphthalen-1-ylmethyl)-methyl-amine 146-147° C. (TFA Salt) 41

(6-Benzenesulfonyl-1,2,3,4-tetrahydro- naphthalen-1-ylmethyl)-urea 34542

2-(6-Benzenesulfonyl-7-methoxy- 1,2,3,4-tetrahydro-naphthalen-1-yl)-ethylamine 346 43

C-[6-(3-Fluoro-benzenesulfonyl)- 1,2,3,4-tetrahydro-naphthalen-1-yl]-methylamine 320 44

[2-(6-Benzenesulfonyl-7-methoxy- 1,2,3,4-tetrahydro-naphthalen-1-yl)-ethyl]-methyl-amine 360 45

N-[2-(6-Benzenesulfonyl-1,2,3,4- tetrahydro-naphthalen-1-yl)-acetyl]-guanidine 372 46

[6-(3-Fluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]- methyl-amine 334 47

Ethyl-[6-(3-fluoro-benzenesulfonyl)- 1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-amine 348 48

(R)-C-(6-Benzenesulfonyl-1,2,3,4- tetrahydro-naphthalen-1-yl)-methylamine 302 49

(R)-C-[6-(3-Methoxy-benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]- methylamine 188-189° C. (HCl Salt)50

(R)-[6-(3-Methoxy-benzenesulfonyl)- 1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-methyl-amine 194-195° C. (HCl Salt) 51

(R)-C-[6-(3-Fluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]- methylamine 320 52

(R)-3-(5-Aminomethyl-5,6,7,8- tetrahydro-naphthalene-2-sulfonyl)-benzonitrile 212-213° C. (Oxalate Salt) 53

(R)-[6-(3-Fluoro-benzenesulfonyl)- 1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-urea 363 54

(R)-C-[6-(1H-Indole-3-sulfonyl)-1,2,3,4- tetrahydro-naphthalen-1-yl]-methylamine 341 55

(R)-2-{[6-(3-Fluoro-benzenesulfonyl)- 1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-amino}-3,5-dihydro-imidazol- 4-one 402 56

(R)-C-(6-Benzenesulfonyl-8-fluoro- 1,2,3,4-tetrahydro-naphthalen-1-yl)-methylamine 248-249° C (HCl Salt) 57

(R)-N-{2-[6-(3-Fluoro- benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-acetyl}-guanidine 390 58

(R)-(6-Benzenesulfonyl-1,2,3,4- tetrahydro-naphthalen-1-ylmethyl)-urea345 59

(R)-C-[6-(1H-Pyrrole-3-sulfonyl)- 1,2,3,4-tetrahydro-naphthalen-1-yl]-methylamine 291 60

(R)-(6-Benzenesulfonyl-8-fluoro- 1,2,3,4-tetrahydro-naphthalen-1-ylmethyl)-methyl-amine 334 61

(R)-1H-Imidazole-2-carboxylic acid [6-(3-fluoro-benzenesulfonyl)-1,2,3,4- tetrahydro-naphthalen-1-ylmethyl]-amide 414 62

(R)-2-(6-Benzenesulfonyl-1,2,3,4- tetrahydro-naphthalen-1-yl)-acetamide330 63

(R)-1H-Pyrrole-2-carboxylic acid [6-(3- fluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]- amide 413 64

(R)-C-(6-Benzenesulfonyl-5-fluoro- 1,2,3,4-tetrahydro-naphthalen-1-yl)-methylamine 320 65

(R)-C-[6-(3-Methanesulfonyl- benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-methylamine 265-266° C. (HCl Salt) 66

(R)-2-Amino-N-[6-(3-fluoro- benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-acetamide 377 67

(R)-C-[6-(1H-Pyrazole-4-sulfonyl)- 1,2,3,4-tetrahydro-naphthalen-1-yl]-methylamine 181-182° C. (HCl Salt) 68

(R)-C-[6-(6-Fluoro-3H-benzoimidazole- 4-sulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-methylamine 360 69

(R)-C-[6-(1-Methyl-1H-imidazole-2-sulfonyl)-1,2,3,4-tetrahydro-naphthalen- 1-yl]-methylamine 196-197° C.(Oxalate Salt) 70

(R)-N-[6-(3-Fluoro-benzenesulfonyl)- 1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-2-methylamino-acetamide 391 71

(R)-1-[6-(3-Fluoro-benzenesulfonyl)- 1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-3-methyl-urea 377 72

(R)-{[6-(2-Fluoro-benzenesulfonyl)- 1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-amino}-acetic acid ethyl ester 406 73

(R)-Methyl-[6-(1H-pyrrole-3-sulfonyl)- 1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-amine 305 74

(R)-N-[6-(2-Fluoro-benzenesulfonyl)- 1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-N′-cyano-guanidine 387 75

(R)-N-[6-(1H-Indole-3-sulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]- acetamide 383 76

(R)-N-(6-Benzenesulfonyl-8-fluoro- 1,2,3,4-tetrahydro-naphthalen-1-ylmethyl)-acetamide 362 77

(R)-2-{[6-(3-Fluoro-benzenesulfonyl)- 1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-amino}-acetamide 377 78

(R)-2-Dimethylamino-N-[6-(3-fluoro- benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-acetamide 405 79

(R)-C-[6-(5-Fluoro-1H-indole-3- sulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-methylamine 359 80

(R)-Pyrrolidine-2-carboxylic acid (6-benzenesulfonyl-1,2,3,4-tetrahydro- naphthalen-1-ylmethyl)-amide 399 81

(R)-2-{[6-(3-Fluoro-benzenesulfonyl)- 1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-amino}-N-methyl-acetamide 391 82

(R)-Pyrrolidine-2-carboxylic acid [6-(3-fluoro-benzenesulfonyl)-1,2,3,4- tetrahydro-naphthalen-1-ylmethyl]-amide 417 83

(R)-2-{[6-(3-Fluoro-benzenesulfonyl)- 1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-methyl-amino}-acetamide 391 84

(R)-N-[6-(3-Fluoro-benzenesulfonyl)- 1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-methanesulfonamide 398 85

(R)-3-[6-(3-Fluoro-benzenesulfonyl)- 1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-1,1-dimethyl-urea 391 86

(R)-N-[6-(3-Fluoro-benzenesulfonyl)- 1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-acetamide 362 87

(R)-1-[6-(3-Fluoro-benzenesulfonyl)- 1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-1-methyl-urea 377 88

(R)-[6-(3-Fluoro-benzenesulfonyl)- 1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-carbamic acid methyl ester 378 89

(R)-Methyl-[6-(1-methyl-1H-pyrrole-3-sulfonyl)-1,2,3,4-tetrahydro-naphthalen- 1-ylmethyl]-amine 319 90

(R)-3-(5-Aminomethyl-5,6,7,8- tetrahydro-naphthalene-2-sulfonyl)- phenol318 91

(R)-N-[6-(3-Fluoro-benzenesulfonyl)- 1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-2-hydroxy-acetamide 378 92

(R)-N-[6-(3-Fluoro-benzenesulfonyl)- 1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-N-methyl-acetamide 376 93

6-Benzenesulfonyl-1,2,3,4-tetrahydro- naphthalene-1-carboxylic acidamide 316 94

(R)-6-Benzenesulfonyl-1,2,3,4- tetrahydro-naphthalene-1-carboxylic acidamide 399 95

(R)-2-{[6-(3-Fluoro-benzenesulfonyl)- 1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-amino}-ethano] 364

Another aspect of the invention provides a composition comprising atherapeutically effective amount of at least one compound of formula (I)and a pharmaceutically acceptable carrier.

Yet another aspect of the invention provides a method for treating acentral nervous system (CNS) disease state in a subject comprisingadministering to the subject a therapeutically effective amount of acompound of formula I. The disease state may comprise, for example,psychoses, schizophrenia, manic depressions, neurological disorders,memory disorders, attention deficit disorder, Parkinson's disease,amyotrophic lateral sclerosis, Alzheimer's disease or Huntington'sdisease.

Still another aspect of the present invention provides a method fortreating a disorder of the gastrointestinal tract in a subjectcomprising administering to the subject a therapeutically effectiveamount of a compound of formula (I).

Another aspect of the present invention provides a method for producinga compound of formula (I).

Synthesis

Compounds of the present invention can be made by a variety of methodsdepicted in the illustrative synthetic reaction schemes shown anddescribed below.

The starting materials and reagents used in preparing these compoundsgenerally are either available from commercial suppliers, such asAldrich Chemical Co., or are prepared by methods known to those skilledin the art following procedures set forth in references such as Fieserand Fieser's Reagents for Organic Synthesis; Wiley & Sons: New York,1991, Volumes 1-15; Rodd's Chemistry of Carbon Compounds, ElsevierScience Publishers, 1989, Volumes 1-5 and Supplementals; and OrganicReactions, Wiley & Sons: New York, 2004, Volumes 1-56. The followingsynthetic reaction schemes are merely illustrative of some methods bywhich the compounds of the present invention can be synthesized, andvarious modifications to these synthetic reaction schemes can be madeand will be suggested to one skilled in the art having referred to thedisclosure contained in this Application.

The starting materials and the intermediates of the synthetic reactionschemes can be isolated and purified if desired using conventionaltechniques, including but not limited to, filtration, distillation,crystallization, chromatography, and the like. Such materials can becharacterized using conventional means, including physical constants andspectral data.

Unless specified to the contrary, the reactions described hereinpreferably are conducted under an inert atmosphere at atmosphericpressure at a reaction temperature range of from about −78° C. to about150° C., more preferably from about 0° C. to about 125° C., and mostpreferably and conveniently at about room (or ambient) temperature,e.g., about 20° C.

Scheme A below illustrates one synthetic procedure usable to preparecompounds of the invention, wherein Ar, m, p, q and R¹ are as definedherein. Numerous synthetic routes to indane and tetralin compounds areknown and may be used in preparation of the subject compounds, and theprocedure of Scheme A is only exemplary. Specific examples of theprocedure of Scheme A are provided in the following Experimentalsection.

In step 1 of Scheme A, ketone compound a undergoes analkylation/cyanylation reaction to give an arylsulfonyl nitrile compoundb. Ketone compound may comprise, for example, an arylsulfonyl indanonewhere q is 2 and p 1, an arylsulfonyl tetralinone where q is 2 and p is2, an arylsulfonyl benzoazepinone where q is 2 and p is 3, or likeketone in accordance with the invention. Corresponding, arylsulfanyl(q=0) and arylsulfinyl (q=1) ketone compounds may be used in this step.Ketone compounds a may be prepared by a variety of techniques known inthe art, and specific examples of preparing such compounds are providedbelow in the Experimental section of this disclosure. The alkylationreaction of step 1 may be achieved by treatment of ketone compound awith trimethylsilyl cyanide in the presence of zinc iodide under polaraprotic solvent conditions, followed by treatment with p-toluenesulfonic acid or like acid.

In step 2, arylsulfonyl nitrile compound is subject to reduction toprovide nitrile compound c. This reduction removes a residualunsaturation resulting from step 1, and may be carried out usinghydrogen gas with a platinum or palladium catalyst.

A second reduction reaction is carried out in step 3 to reduce thenitrile group of compound c and afford an arylsulfonyl aminomethylcompound d. Compound d is a compound of formula I in accordance with theinvention.

Many variations on the procedure of Scheme A are possible and will bereadily apparent to those skilled in the art. In certain embodiments thereduction reactions of step 2 and step 3 may be performed in a singlestep. In other embodiments, the reduction of step 2 may be omitted toprovide an additional unsaturation. The amine compound d may be subjectto additional alkylation reaction, using suitableprotection/deprotection to afford monoalkylamino or dialkylaminocompounds. Amine compound d may also undergo subsequent reaction to formamidinyl, guanidinyl, imidazolinyl, imidazolinylamino, and otherfunctionalities. Specific examples of such additional reactions areprovided in the Examples below.

Referring to Scheme B, another synthetic route for the subject compoundsis shown, wherein X is a leaving group and may be the same or differentin each occurrence, R is lower alkyl and may be the same or different ineach occurrence, and Ar, m, n, p, q, R¹, R³ and R⁴ are as definedherein.

In step 1 of Scheme B, ketone compound a is subject to an alkylationreaction to afford a hydroxy ester compound e. Ketone compound a may beany one of a variety of arylsulfonyl, arylsulfanyl or arylsulfinylindanone and tetralinone compounds as noted above. Alkylation in step 1may be effected by treatment of ketone compound a with zinc and iodine,followed by a haloalkyl ester compound such as ethyl bromopropionate(where X is bromo, n is 1, R³ and R⁴ are hydrogen, and R is ethyl).

In step 2, hydroxy ester compound e is dehydrated by treatment with acidsuch as para-toluenesulfonic acid, to yield an unsaturated estercompound f. In certain embodiments the dehydration of step 2 may occurspontaneously during step 1, and thus step 2 may be omitted.

A reduction reaction takes place in step 3 in which the residualunsaturation in compound f is hydrogenated by treatment with hydrogen inthe presence of a suitable platinum or palladium catalyst, to provideester compound g.

In step 4, the compound g is subject to reduction, followed byalkylsulfonylation, to afford sulfonate compound h. This step may becarried out by treatment of compound g with reducing agent such aslithium aluminum hydride to form an alcohol (not shown), which is thentreated with alkylsulfonyl halide such as methanesulfonyl chloride.

Amination of arylsulfonate compound h in step 5 provides amine compoundi. This amination in many embodiments may comprise treatment ofsulfonate compound h with sodium azide to form an azido compound (notshown), which is then reduced, using lithium aluminum hydride or likereducing agent, followed by acid workup to yield amine i.

As in the case of Scheme A, many variations on the procedure of Scheme Bare possible and will suggest themselves to those skilledin the art. Inon such variation, sulfonate compound h may be treated with cyanide toform a nitrile compound, which in turn is reduced to provide an amine.Amino compound i may be subject to further reaction to affordmonoalkylamino, dialkylamino, amidinyl, guanidinyl, imidazolinyl,imidazolinylamino, and other functionalities as related above. Specificdetails for producing compounds of formula I are described in theExamples section below.

Utility

The compounds of the invention have selective affinity for 5-HTreceptors, including the 5-HT₆ the 5-HT_(2A) receptor, or both, and assuch are expected to be useful in the treatment of certain CNS disorderssuch as Parkinson's disease, Huntington's disease, anxiety, depression,manic depression, psychosis, epilepsy, obsessive compulsive disorders,mood disorders, migraine, Alzheimer's disease (enhancement of cognitivememory), sleep disorders, feeding disorders such as anorexia, bulimia,and obesity, panic attacks, akathisia, attention deficit hyperactivitydisorder (ADHD), attention deficit disorder (ADD), withdrawal from drugabuse such as cocaine, ethanol, nicotine and benzodiazepines,schizophrenia, and also disorders associated with spinal trauma and/orhead injury such as hydrocephalus. Such compounds are also expected tobe of use in the treatment of certain GI (gastrointestinal) disorderssuch functional bowel disorder and irritable bowel syndrome.

Testing

The pharmacology of the compounds of this invention was determined byart recognized procedures. The in vitro techniques for determining theaffinities of test compounds at the 5-HT6 receptor and the 5-HT2Areceptor in radioligand binding and functional assays are describedbelow.

Administration and Pharmaceutical Composition

The present invention includes pharmaceutical compositions comprising atleast one compound of the present invention, or an individual isomer,racemic or non-racemic mixture of isomers or a pharmaceuticallyacceptable salt or solvate thereof, together with at least onepharmaceutically acceptable carrier, and optionally other therapeuticand/or prophylactic ingredients.

In general, the compounds of the present invention will be administeredin a therapeutically effective amount by any of the accepted modes ofadministration for agents that serve similar utilities. Suitable dosageranges are typically 1-500 mg daily, preferably 1-100 mg daily, and mostpreferably 1-30 mg daily, depending upon numerous factors such as theseverity of the disease to be treated, the age and relative health ofthe subject, the potency of the compound used, the route and form ofadministration, the indication towards which the administration isdirected, and the preferences and experience of the medical practitionerinvolved. One of ordinary skill in the art of treating such diseaseswill be able, without undue experimentation and in reliance uponpersonal knowledge and the disclosure of this Application, to ascertaina therapeutically effective amount of the compounds of the presentinvention for a given disease.

In general, compounds of the present invention will be administered aspharmaceutical formulations including those suitable for oral (includingbuccal and sub-lingual), rectal, nasal, topical, pulmonary, vaginal, orparenteral (including intramuscular, intraarterial, intrathecal,subcutaneous and intravenous) administration or in a form suitable foradministration by inhalation or insufflation. The preferred manner ofadministration is generally oral using a convenient daily dosage regimenwhich can be adjusted according to the degree of affliction.

A compound or compounds of the present invention, together with one ormore conventional adjuvants, carriers, or diluents, may be placed intothe form of pharmaceutical compositions and unit dosages. Thepharmaceutical compositions and unit dosage forms may be comprised ofconventional ingredients in conventional proportions, with or withoutadditional active compounds or principles, and the unit dosage forms maycontain any suitable effective amount of the active ingredientcommensurate with the intended daily dosage range to be employed. Thepharmaceutical compositions may be employed as solids, such as tabletsor filled capsules, semisolids, powders, sustained release formulations,or liquids such as solutions, suspensions, emulsions, elixirs, or filledcapsules for oral use; or in the form of suppositories for rectal orvaginal administration; or in the form of sterile injectable solutionsfor parenteral use. Formulations containing about one (1) milligram ofactive ingredient or, more broadly, about 0.01 to about one hundred(100) milligrams, per tablet, are accordingly suitable representativeunit dosage forms.

The compounds of the present invention may be formulated in a widevariety of oral administration dosage forms. The pharmaceuticalcompositions and dosage forms may comprise a compound or compounds ofthe present invention or pharmaceutically acceptable salts thereof asthe active component. The pharmaceutically acceptable carriers may beeither solid or liquid. Solid form preparations include powders,tablets, pills, capsules, cachets, suppositories, and dispersiblegranules. A solid carrier may be one or more substances which may alsoact as diluents, flavouring agents, solubilizers, lubricants, suspendingagents, binders, preservatives, tablet disintegrating agents, or anencapsulating material. In powders, the carrier generally is a finelydivided solid which is a mixture with the finely divided activecomponent. In tablets, the active component generally is mixed with thecarrier having the necessary binding capacity in suitable proportionsand compacted in the shape and size desired. The powders and tabletspreferably contain from about one (1) to about, seventy (70) percent ofthe active compound. Suitable carriers include but are not limited tomagnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin,dextrin, starch, gelatine, tragacanth, methylcellulose, sodiumcarboxymethylcellulose, a low melting wax, cocoa butter, and the like.The term “preparation” is intended to include the formulation of theactive compound with encapsulating material as carrier, providing acapsule in which the active component, with or without carriers, issurrounded by a carrier, which is in association with it. Similarly,cachets and lozenges are included. Tablets, powders, capsules, pills,cachets, and lozenges may be as solid forms suitable for oraladministration.

Other forms suitable for oral administration include liquid formpreparations including emulsions, syrups, elixirs, aqueous solutions,aqueous suspensions, or solid form preparations which are intended to beconverted shortly before use to liquid form preparations. Emulsions maybe prepared in solutions, for example, in aqueous propylene glycolsolutions or may contain emulsifying agents, for example, such aslecithin, sorbitan monooleate, or acacia. Aqueous solutions can beprepared by dissolving the active component in water and adding suitablecolorants, flavors, stabilizers, and thickening agents. Aqueoussuspensions can be prepared by dispersing the finely divided activecomponent in water with viscous material, such as natural or syntheticgums, resins, methylcellulose, sodium carboxymethylcellulose, and otherwell known suspending agents. Solid form preparations include solutions,suspensions, and emulsions, and may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

The compounds of the present invention may be formulated for parenteraladministration (e.g., by injection, for example bolus injection orcontinuous infusion) and may be presented in unit dose form in ampoules,pre-filled syringes, small volume infusion or in multi-dose containerswith an added preservative. The compositions may take such forms assuspensions, solutions, or emulsions in oily or aqueous vehicles, forexample solutions in aqueous polyethylene glycol. Examples of oily ornonaqueous carriers, diluents, solvents or vehicles include propyleneglycol, polyethylene glycol, vegetable oils (e.g., olive oil), andinjectable organic esters (e.g., ethyl oleate), and may containformulatory agents such as preserving, wetting, emulsifying orsuspending, stabilizing and/or dispersing agents. Alternatively, theactive ingredient may be in powder form, obtained by aseptic isolationof sterile solid or by lyophilization from solution for constitutionbefore use with a suitable vehicle, e.g., sterile, pyrogen-free water.

The compounds of the present invention may be formulated for topicaladministration to the epidermis as ointments, creams or lotions, or as atransdermal patch. Ointments and creams may, for example, be formulatedwith an aqueous or oily base with the addition of suitable thickeningand/or gelling agents. Lotions may be formulated with an aqueous or oilybase and will in general also containing one or more emulsifying agents,stabilizing agents, dispersing agents, suspending agents, thickeningagents, or coloring agents. Formulations suitable for topicaladministration in the mouth include lozenges comprising active agents ina flavored base, usually sucrose and acacia or tragacanth; pastillescomprising the active ingredient in an inert base such as gelatine andglycerine or sucrose and acacia; and mouthwashes comprising the activeingredient in a suitable liquid carrier.

The compounds of the present invention may be formulated foradministration as suppositories. A low melting wax, such as a mixture offatty acid glycerides or cocoa butter is first melted and the activecomponent is dispersed homogeneously, for example, by stirring. Themolten homogeneous mixture is then poured into convenient sized molds,allowed to cool, and to solidify.

The compounds of the present invention may be formulated for vaginaladministration. Pessaries, tampons, creams, gels, pastes, foams orsprays containing in addition to the active ingredient such carriers asare known in the art to be appropriate.

The compounds of the present invention may be formulated for nasaladministration. The solutions or suspensions are applied directly to thenasal cavity by conventional means, for example, with a dropper, pipetteor spray. The formulations may be provided in a single or multidoseform. In the latter case of a dropper or pipette, this may be achievedby the patient administering an appropriate, predetermined volume of thesolution or suspension. In the case of a spray, this may be achieved forexample by means of a metering atomizing spray pump.

The compounds of the present invention may be formulated for aerosoladministration, particularly to the respiratory tract and includingintranasal administration. The compound will generally have a smallparticle size for example of the order of five (5) microns or less. Sucha particle size may be obtained by means known in the art, for exampleby micronization. The active ingredient is provided in a pressurizedpack with a suitable propellant such as a chlorofluorocarbon (CFC), forexample, dichlorodifluoromethane, trichlorofluoromethane, ordichlorotetrafluoroethane, or carbon dioxide or other suitable gas. Theaerosol may conveniently also contain a surfactant such as lecithin. Thedose of drug may be controlled by a metered valve. Alternatively theactive ingredients may be provided in a form of a dry powder, forexample a powder mix of the compound in a suitable powder base such aslactose, starch, starch derivatives such as hydroxypropylmethylcellulose and polyvinylpyrrolidine (PVP). The powder carrier will form agel in the nasal cavity. The powder composition may be presented in unitdose form for example in capsules or cartridges of e.g., gelatine orblister packs from which the powder may be administered by means of aninhaler.

When desired, formulations can be prepared with enteric coatings adaptedfor sustained or controlled release administration of the activeingredient. For example, the compounds of the present invention can beformulated in transdermal or subcutaneous drug delivery devices. Thesedelivery systems are advantageous when sustained release of the compoundis necessary and when patient compliance with a treatment regimen iscrucial. Compounds in transdermal delivery systems are frequentlyattached to an skin-adhesive solid support. The compound of interest canalso be combined with a penetration enhancer, e.g., Azone(1-dodecylazacycloheptan-2-one). Sustained release delivery systems areinserted subcutaneously into the subdermal layer by surgery orinjection. The subdermal implants encapsulate the compound in a lipidsoluble membrane, e.g., silicone rubber, or a biodegradable polymer,e.g., polylactic acid.

The pharmaceutical preparations are preferably in unit dosage forms. Insuch form, the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

Other suitable pharmaceutical carriers and their formulations aredescribed in Remington: The Science and Practice of Pharmacy 1995,edited by E. W. Martin, Mack Publishing Company, 19th edition, Easton,Pa. Representative pharmaceutical formulations containing a compound ofthe present invention are described in the Examples below.

EXAMPLES

The following preparations and examples are given to enable thoseskilled in the art to more clearly understand and to practice thepresent invention. They should not be considered as limiting the scopeof the invention, but merely as being illustrative and representativethereof. The following abbreviations may be used in the Examples.

Abbreviations

-   DCM dichloromethane/methylene chloride-   DMF N,N-dimethylformamide-   DMAP 4-dimethylaminopyridine-   EtOAc ethyl acetate-   EtOH ethanol-   tBuOH tert-butanol-   gc gas chromatography-   HMPA hexamethylphosphoramide-   hplc high performance liquid chromatography-   mCPBA m-chloroperbenzoic acid-   MeCN acetonitrile-   NMP N-methyl pyrrolidinone-   TEA triethylamine-   TFA trifluoroacetic acid-   THF tetrahydrofuran-   LDA lithium diisopropylamine-   TLC thin layer chromatography

Preparation 1 6-Benzenesulfonyl-3,4-dihydro-2H-naphthalen-1-one

The synthetic procedure described in this Preparation was carried outaccording to the process shown in Scheme C.

Step 1 4-(3-Fluoro-phenyl)-4-oxo-butyric acid methyl ester

A solution of 3-fluorobenzaldehyde (35.38 g, 285.07 mmol) in 35 mLdimethylformamide (DMF) was added to a heated (48° C.) solution ofmethyl acrylate (26.28 mL, 25.03 g, 290.7 mmol) and powdered KCN underArgon. The reaction mixture was stirred at 40° C. for 2 hours and thenpoured into 500 mL of water. This aqueous phase was extracted twice with500 mL of Et₂O and once with 250 mL of EtOAc. The combined organiclayers were washed with water and saturated brine, and then dried overMgSO₄. The solvent was evaporated under reduced pressure to give 50.89 g(242.2 mmol, 84.93%) of 4-(3-fluoro-phenyl)-4-oxo-butyric acid methylester as an oil. MS: 211 (M+H)⁺.

Step 2 4-(3-Fluoro-phenyl)-butyric acid

A solution of 4-(3-fluoro-phenyl)-4-oxo-butyric acid methyl ester (28.27g, 134.49 mmol), hydrazine monohydrate (26.1 mL, 26.93 g, 537.96 mmol)and KOH (22.64 g, 403.47 mmol) in ethylene glycol (150 mL) was heated toreflux under argon and refluxed for 2 hours. The reaction mixture wascooled and diluted with 1.5 litres of water, 500 mL of Et₂O was added,and the mixtures was acidified by addition of 6 M HCl with stirring,after which an additional 500 mL of Et₂O was added. The organic layerwas removed and the aqueous layer was extracted twice with 250 mL of 500mL of Et₂O/EtOAc (3:1). The combined organic layers were washed withwater, saturated brine, and then dried over MgSO₄. The solvent wasevaporated under reduced pressure to yield a brownish oil, which waseluted through silica gel using hexanes/EtOAc (9:1). Removal of solventunder reduced pressure yielded 18.44 g (101.21 mmol, 75.26%) of4-(3-fluoro-phenyl)-butyric acid as an oil. MS: 183 (M+H)⁺.

Step 3 6-Fluoro-3,4-dihydro-2H-naphthalen-1-one

A solution of methanesulfonic acid (75 mL) and P₂O₅ was stirred at 85°C. for 15 minutes, at which point most of the P₂O₅ had dissolved. Anadditional 15 mL of methanesulfonic acid was added dropwise, and themixture was stirred at 85° C. for 2 hours. The reaction mixture waspoured into 500 mL of water and extracted twice with 400 mL of EtOAc.The combined organic layers were washed with saturated NaHCO₃, water,and saturated brine, and then dried over MgSO₄. The solvent was removedunder reduced pressure to give an oil that was eluted through silica gelusing hexanes/EtOAc (9:1). Removal of solvent under reduced pressureyielded 6.06 g, 36.91 mmol, 53.97%) of6-fluoro-3,4-dihydro-2H-naphthalen-1-one as a yellow oil. MS: 165(M+H)⁺.

Step 4 6-Phenylsulfanyl-3,4-dihydro-2H-naphthalen-1-one

A solution of 6-fluoro-3,4-dihydro-2H-naphthalen-1-one (5.51 g, 33.56mmol), benzenethiol (4.07 g, 3.79 mL, 36.92 mmol) and K₂CO₃ (9.28 g,67.12 mmol) in 50 mL of N-methyl pyrrolidinone (NMP) was heated to 80°C. under argon and stirred at 80° C. for 2 hours. The reaction mixturewas poured into 500 mL of water and diluted with 300 mL of EtOAc. Thelayers were separated and the aqueous layer was extracted twice with 250mL of EtOAc. The combined organic layers were washed with water,saturated brine, and then dried over MgSO₄. The solvent was removedunder reduced pressure to yield an oil which was eluted through silicagel using hexanes/EtOAc (9:1). Removal of solvent under reduced pressureprovided 8.05 g (31.65 mmol, 94.31%) of6-phenylsulfanyl-3,4-dihydro-2H-naphthalen-1-one as a pale yellow oil.MS: 255 (M+H)⁺.

Step 5 6-Benzenesulfonyl-3,4-dihydro-2H-naphthalen-1-one

A solution of 6-phenylsulfanyl-3,4-dihydro-2H-naphthalen-1-one (8.05 g,31.65 mmol) in MeOH/MeCN (50 mL of each) was stirred at roomtemperature. OXONE™ (potassium peroxymonosulfate, 77.83 g, 126.60 mmol)was dissolved in 50 mL of water and was added to the stirring reaction.The reaction mixture was stirred for 15 hours, and then evaporated underreduced pressure. The resulting aqueous residue was diluted with 500 mLof water and extracted three times with 300 mL of EtOAc. The combinedextracts were washed with water, saturated brine, and dried over MgSO₄.The solvent was removed under reduced pressure to yield an oil which waseluted through silica gel with hexane followed by chloroform. Removal ofsolvent under reduced pressure afforded 6.55 g (22.87 mmol, 72.27%) of awhite solid, which was recrystallized from EtO₂/hexanes. MS: 287 (M+H)⁺.

Similarly prepared using the above procedure with 3-chlorobenzenethiolin step 4, was6-(3-chloro-benzenesulfonyl)-3,4-dihydro-2H-naphthalen-1-one. MS: 287(M+H)⁺.

Preparation 2 7-Benzenesulfonyl-3,4-dihydro-2H-naphthalen-1-one

The synthetic procedure described in this Preparation was carried outaccording to the process shown in Scheme D.

Step 1: 4-(4-Fluoro-phenyl)-4-oxo-butyric acid

Fluorobenzene (50 mL, 530 mmol) and aluminum trichloride (156 g, 1.17mol) were added to 500 mL of methylene chloride, and the reactionmixture was stirred. Succinic anhydride (50 g, 500 mmol) was added tothe stirring reaction mixture all at once, and the reaction mixture wasstirred at room temperature for 2 hours. The reaction was quenched bycautious addition of 10% HCl, and the reaction mixture was added to 500mL of water. The aqueous mixture was extracted twice with 250 mL ofmethylene chloride, and the combined organic layers were dried (Mg SO₄),and evaporated under reduced pressure to give 62 g (316 mmol, 59.6%) of4-(4-fluoro-phenyl)-4-oxo-butyric acid as a crude solid. MS: 197 (M+H)⁺.

Step 2: 4-Oxo-4-(4-phenylsulfanyl-phenyl)-butyric acid

4-(4-Fluoro-phenyl)-4-oxo-butyric acid (10.0 g, 51mmol), thiophenol (5.2g, 51 mmol), thiophenol (5.2 g, 51 mmol) and powdered potassiumcarbonate (13.8 g, 100 mmol) were added to 25 mL of dimethyl sulfoxide(DMSO). The reaction mixture was heated to 110° C. for 2 hours, thencooled and diluted by addition of 250 mL water. The aqueous mixture wasextracted three times with 100 mL of EtOAc, and the combined organiclayers were dried (MgSO₄), and evaporated under reduced pressure toyield 11 g (38.5 mmol, 75.5%) of4-oxo-4-(4-phenylsulfanyl-phenyl)-butyric acid as a crude solid. MS: 287(M+H)⁺.

Step 3: 4-(4-Phenylsulfanyl-phenyl)-butyric acid

Powdered Zinc (66 g) was washed with 2% HCl, added to a solution ofHgC1₂ (6 g) in 50 mL of 6M HCl. This mixture was shaken vigorously for 5minutes, and excess liquid was decanted. The mixture was then added to amechanically stirred suspension of4-oxo-4-(4-phenylsulfanyl-phenyl)-butyric acid (6.5 g, 22.7 mmol) in 450mL of 6M HCl, and the reaction mixture was stirred at room temperaturefor 5 days. The mixture was then decanted to remove excess HCl, andquenched by addition of 250 mL water. The aqueous mixture was extractedthree times with 100 mL of EtOAc, and the combined organic layers weredried under reduced pressure to yield 5.0 g (18.4 mmol, 81%) of4-(4-phenylsulfanyl-phenyl)-butyric acid as a crude solid. MS: 273(M+H)⁺.

Step 4: 7-Phenylsulfanyl-3,4-dihydro-2H-naphthalen-1-one

4-(4-Phenylsulfanyl-phenyl)-butyric acid (5.0 g, 18.4 mmol) wasdissolved in 50 mL tetrahydrofuran (THF). Oxalyl chloride (1.8 mL, 20mmol) and one drop of DMF were added, and the reaction mixture wasstirred for 1 hour, and then evaporated to dryness under reducedpressure. The resulting residue was dissolved in 40 mL of1,2-dichloroethane, and aluminum trichloride (0.85 g, 25 mmol) was addedall at once. The reaction mixture was stirred for 1 hour, and quenchedby addition of 2% HCl. This aqueous mixture was extracted twice with 100mL of EtOAc, and the combined organic layers were dried (MgSO₄) andevaporated to yield 2.54 g (10 mmol, 55.5%) of7-phenylsulfanyl-3,4-dihydro-2H-naphthalen-1-one as a gummy residue. MS:255 (M+H)⁺.

Step 5: 7-Benzenesulfonyl-3,4-dihydro-2H-naphthalen-1-one

7-Phenylsulfanyl-3,4-dihydro-2H-naphthalen-1-one ( ) was dissolved in 50mL of MeOH and stirred at room temperature. OXONE™ (13.5 g, 22 mmol) wasdissolved in 10 mL of water and added to the stirring reaction. Thereaction mixture was stirred for 8 hours, and then evaporated underreduced pressure. The resulting aqueous residue was diluted with 200 mLof water and extracted three times with 100 mL of EtOAc. The combinedextracts were dried over MgSO₄, and the solvent was removed underreduced pressure to yield an oil which was eluted through silica gelwith 1:1 EtOAc/hexanes. Removal of solvent under reduced pressureafforded 1.7 g (5.9 mmol, 59%) of7-benzenesulfonyl-3,4-dihydro-2H-naphthalen-1-one as an oil. MS: 287(M+H)⁺.

Similarly prepared using the above procedure with 4-fluorobenzenethiolin step 2, was7-(4-fluoro-benzenesulfonyl)-3,4-dihydro-2H-naphthalen-1-one. MS: 287(M+H)⁺.

Preparation 3 5-Phenylsulfonyl-indan-1-one

The synthetic procedure described in this Preparation was carried outaccording to the process shown in Scheme E.

Step 1: 5-Phenylsulfanyl-indan-1-one

5-Fluoro-1-indanone from Aldrich Sigma Chemical Co. (Cat No. 18,566-3)was treated with benzenethiol in the presence of potassium carbonateusing the procedure of step 4 of Example 1 to afford5-phenylsulfanyl-indan-1-one. MS: 241 (M+H)⁺.

Step 2: 5-Phenylsulfonyl-indan-1-one

5-Phenylsulfanyl-indan-1-one was treated with OXONE™ using the procedureof step 5 of Preparation 1 to afford 5-phenylsulfonyl-indan-1-one. MS:273 (M+H)⁺.

Example 1C-(6-Benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-methylamine

The synthetic procedure described in this Example was carried outaccording to the process shown in Scheme F.

Step 1 6-Benzenesulfonyl-3,4-dihydro-naphthalene-1-carbontrile

6-Benzenesulfonyl-3,4-dihydro-2H-naphthalen-1-one from Preparation 1above (4.0 g, 14 mmol), trimethylsilyl cyanide (10.0 g, 100 mmol) andZinc Iodide (0.25 g) were combined and stirred under nitrogen for 15hours. The reaction mixture was then diluted by addition of 200 mL ofEt₂O, washed with cold water, and the organic layer was dried (MgSO₄)and evaporated under reduced pressure to an oil. The oil was dissolvedin 250 mL of toluene, and 0.5 g of paratoluene sulfonic acid was added.The reaction mixture was refluxed for three hours, cooled, and the thesolvent was removed under reduced pressure. The crude product was elutedthrough silica under medium pressure with 5% EtOAc in hexanes to yield1.8 g (6.1 mmol, 44%) of (racemic)6-benzenesulfonyl-3,4-dihydro-naphthalene-1-carbonitrile as an oil. MS:296 (M+H)⁺.

Step 2 6-Benzenesulfonyl-1,2,3,4-tetrahydro-naphthalene-1-carbonitrile

6-Benzenesulfonyl-3,4-dihydro-naphthalene-1-carbonitrile (5.1 g, 17.2mmol), 70 mL EtOH, and 50 mL acetic acid were placed in a Parr vessel,and 1.0 g of 10% Palladium on carbon (Fluka Chemica Co.) was added. Thereaction mixture was shaken for 15 hours under 55 psi hydrogen. The Parrvessel was purged with nitrogen and the reaction mixture was filtered.The filtrate was added to 500 mL water, and the aqueous mixture wasextracted twice with 200 mL of EtOAc. The combined organic layers weredried (MgSO₄) and evaporated to yield 4.6 g (15.5 mmol, 90%) of6-benzenesulfonyl-1,2,3,4-tetrahydro-naphthalene-1-carbonitrile as anoil. MS: 298 (M+H)⁺.

Step 3C-(6-Benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-methylamine

6-Benzenesulfonyl-1,2,3,4-tetrahydro-naphthalene-1-carbonitrile wasdissolved in 100 mL of dry tetrahydrofuran (THF), and the mixture wasstirred while cooling in an ice bath. Borane-THF complex (40 mL) wasadded to the cold, stirring solution, and the reaction mixture wasstirred under nitrogen for 15 hours at room temperature. The reactionmixture was carefully quenched by addition of 20 mL of 20% HCl and 60 mLof methanol. The solvents were removed under reduced pressure, and theaqueous residue was treated dropwise with 1M NaOH until basic. Theresidue was extracted twice with 100 mL of EtOAc and the organic layerswere dried (MgSO₄) and evaporated. The crude product was acidified withdilute HCl in EtOH and recrystallized from EtOAc to yield 3.1 g ofC-(6-benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-methylamine asa hydrochloride salt. MS: 302 (M+H)⁺.

Similarly prepared, using the appropriate naphthalenone compound in step1, were:

2-(7-Benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-ethylamine, MS:302 (M+H)⁺;

C-[6-(3-Chloro-benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-methylamine,MS: 337 (M+H)⁺; and

C-[7-(4-Fluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-methylamine,MS: 320 (M+H)⁺.

Example 2[6-(3-Chloro-benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-methyl-amine

The synthetic procedure described in this Example was carried outaccording to the process shown in Scheme G.

C-[6-(3-Chloro-benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-methylamine(1.1 g, 3.2 mmol) and di-tert-butyl dicarbonate (DiBOC, 0.8 g, 3.7 mmol)were dissolved in 50 mL of dry THF, and this reaction mixture wasstirred for 3 hours at room temperature (25° C.) under nitrogen. Thesolvent was evaporated under reduced pressure and the residue wasdissolved in 50 mL of Et₂O and filtered. The filtrate was evaporatedunder reduced pressure to yield the BOC-protectedC-[6-(3-chloro-benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-methylamine,which was directly dissolved in dry dimethyl formamide (20 mL) andcooled in an ice bath. Sodium hydride (0.17 g, 60% weight in oil,approx. 4.3 mmol) was washed with hexanes, and the washed solid wasadded to the reaction mixture. The reaction mixture was stirred forthree hours at ice bath temperature, after which 0.25 mL (4.0 mmol) ofiodomethane was added. Stirring was continued for another three hours,and the reaction mixture was by addition of 250 mL of cold 0.5% aqueousHCl. The aqueous mixture was extracted twice with 100 mL of Et₂O, andthe combined organic layers were dried (MgSO₄) and evaporated underreduced pressure to yield an oil. This oil was dissolved in 20 mL of THFand 20 mL of HCl in Et₂O was added. The solvents were evaporated, andthe resulting solid was reqcyrstallized from EtOH-Et₂O to yield 0.3 g of[6-(3-chloro-benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-methyl-amineas a hydrochloride salt. MS: 351 (M+H)⁺.

Example 3N-(6-Benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl)-acetamidine

The synthetic procedure described in this Example was carried outaccording to the process shown in Scheme H.

C-(6-benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-methylamine(0.4 g, 1.32 mmol) and ethyl imidate (acetimidic acid ethyl ester,0.17g, 1.32 mmol) were dissolved in 10 mL of absolute ethanol, and thereaction mixture was stirred for 8 hours under argon at roomtemperature. The solvent was removed under reduced pressure to yield acrude oil, which was recrystallized from Et₂O/EtOH as an oxalate salt.MS: 343 (M+H)⁺.

Example 4N-(6-Benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl)-guanidine

The synthetic procedure described in this Example was carried outaccording to the process shown in Scheme I.

C-(6-Benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-methylamine(1.0 g, 3.5 mmol), 1H-pyrazol-1-carboxamidine hydrochloride (0.5 g, 3.5mmol) and 1.2 mL of diethyl isopropylamine (7.0 nnol) were dissolved in10 mL of DMF. The reaction mixture was heated to 100° C. for three hoursand then cooled and diluted by addition of 75 mL of water. The aqueousmixture was extracted twice with 100 mL of EtOAc, and the combinedorganic layers were dried over MgSO₄. The solvent was removed underreduced pressure, and the resulting oil was purified by medium pressurechromatography (silica gel, MeOH/CHCl₃/NH₄OH 10:89:1) to yield 0.4 g(1.16 mmol, 33%) ofN-(6-benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl)-guanidine,MS: 344 (M+H)⁺.

Example 5(6-Benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl)-(4,5-dihydro-1H-imidazol-2-yl)-amine

The synthetic procedure described in this Example was carried outaccording to the process shown in Scheme J.

C-(6-Benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-methylamine(100 mg, 0.31 mmol) and 2-methylsulfanyl-4,5-dihydro-1H-imidazolehydroiodide (76 mg, 0.31 mmol) were added to 2 mL CH₂Cl₂, and thereaction mixture was heated to gentle reflux until all of the solventwas evaporated. The reaction mixture was heated to 150° C. for 30minutes and then cooled. The crude mixture was basified by dropwiseaddition of aqueous NaOH solution, and then purified by preparativeliquid chromatography (CH₂Cl₂/MeOH 90:10) on a short silica gel column.Removal of the solvent afforded 57 mg (47%) of(6-Benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl)-(4,5-dihydro-1H-imidazol-2-yl)-amine.MS: 370 (M+H)⁺.

Example 6(7-Benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl)-(5,5-dimethyl-1,4,5,6-tetrahydro-pyrimidin-2-yl)-amine

The synthetic procedure described in this Example was carried outaccording to the process shown in Scheme K.

C-(6-Benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-methylamine(0.125 g, 0.41 mmol) and5,5-Dimethyl-2-methylsulfanyl-hexahydro-pyrimidine hydrochloride wereadded to 2 mL CH₂Cl₂, and the reaction mixture was heated to gentlereflux until all of the solvent was evaporated. The reaction mixture washeated to 150° C. for 30 minutes and then cooled. The crude mixture wasbasified by dropwise addition of aqueous NaOH solution, and thenpurified by preparative liquid chromatography (CH₂Cl₂/MeOH 90:10) andrecrystallized from CH₂Cl₂/ether to afford 58 mg (31%) of(7-Benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl)-(5,5-dimethyl-1,4,5,6-tetrahydro-pyrimidin-2-yl)-amine.MP: 140-145° C. MS: 413 (M+H)⁺.

Example 72-(6-Benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-ethylamine

The synthetic procedure described in this Example was carried outaccording to the process shown in Scheme L.

Step 1(6-Benzenesulfonyl-1-hydroxy-1,2,3,4-tetrahydro-naphthalen-1-yl)-aceticacid methyl ester

A solution/suspension of anhydrous benzene (25 mL), powdered Zinc metal(0.505 g, 7.72 mmol), I₂ (0.01 g) and6-benzenesulfonyl-3,4-dihydro-2H-naphthalen-1-one was stirred for 10minutes at room temperature. Ethyl bromopropionate (0.784 mL, 1.18 g,7.07 mmol) was added and the reaction mixture was heated to reflux for2.5 hours. The reaction mixture was allowed to cool, diluted with 300 mLof water and extracted twice with 250 mL of EtOAc. The combined organiclayers were washed with water and saturated brine, dried (MgSO₄) andevaporated under reduced pressure to yield(6-benzenesulfonyl-1-hydroxy-1,2,3,4-tetrahydro-naphthalen-1-yl)-aceticacid methyl ester. MS: 375 (M+H)⁺.

Step 2 (6-Benzenesulfonyl-3,4-dihydro-2H-naphthalen-1-ylidene)-aceticacid methyl ester

A solution of(6-benzenesulfonyl-1-hydroxy-1,2,3,4-tetrahydro-naphthalen-1-yl)-aceticacid methyl ester (1.28 g, 3.42 mmol) and para-toluenesulfonic acid(0.50 g) in 250 mL of benzene was refluxed for 2 hours using aDean-Stark trap. The reaction mixture was cooled and poured into 500 mLof EtOAc, and this organic phase was washed with water, saturatedNaHCO₃, and dried (MgSO₄). Evaporation under reduced pressure gave adark oil that was purified by elution on silica gel (hexanes:EtOAc 7:3)to yield 0.991 g (2.78 mmol, 81.2% of a white crystalline solid. MS: 357(M+H)⁺.

Step 3 (6-Benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-aceticacid methyl ester

(6-Benzenesulfonyl-3,4-dihydro-2H-naphthalen-1-ylidene)-acetic acidmethyl ester (5.63 g, 15.8 mmol) was dissolved in 300 mL EtOAc in a 1 LParr vessel, and 1.0 g of palladium/activated carbon was added. Thereaction mixture was shaken for 8 hours under 50 psi of hydrogen, afterwhich the mixture was filtered through a CELITE™ plug. The filtrate wasevaporated under reduced pressure to give an oil, which was dissolved inhexanes:EtOAc (3:2) and eluted through silica gel to afford 5.22g (14.56mmol, 92.2%) of(6-benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-acetic acidmethyl ester. MS: 359 (M+H)⁺.

Step 4 Methanesulfonic acid2-(6-benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-ethyl ester

A solution of(6-benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-acetic acidmethyl ester (5.22g, 14.56 mmol) in anhydrous Et₂O (50 mL) was cooled to0° C. under argon, and 21.84 mL of lithium aluminum hydride (21.84 mmol)in THF was added dropwise via syringe. An additional 50 mL of dry THFwas added, and the reaction mixture was stirred for 1 hour. The reactionmixture was carefully quenched by addition of 500 mL water, and theresulting aqueous mixture was extracted twice with 250 mL of EtOAc.Evaporation of the organic layer yielded a crude oil which was purifiedby elution through silica gel with 1:1 hexanes:EtOAc. The solvent wasevaporated to give a solid that was dissolved in 50 mL dry methylenechloride. The solution was cooled to 0° C., and pyridine (4.0 mL, 49.5mmol) and methanesulfonyl chloride (1.69 mL, 21.84 mmol) were added. Thereaction mixture was stirred for 3 hours, during which time the reactionmixture was allowed to warm to room temperature. The reaction mixturewas poured into 500 mL of saturated aqueous NaHCO₃, and the mixture wasextracted three times with 250 mL of EtOAc. The combined organic layerswere washed with water, brine, and dried on MgSO₄. The solvent wasremoved under reduced pressure to give an oil that was dissolved inbenzene and azeotroped to remove residual pyridine. Solvent was removed,and the resulting oil was dissolved in methylene chloride and elutedthrough silica gel with 1:1 hexanes:EtOAc. Solvent was again removed, toafford methanesulfonic acid2-(6-benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-ethyl ester asa white solid (4.44 g, 11.25 mmol, 77.3%) MS: 396 (M+H)⁺.

Step 52-(6-Benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-ethylamine

A solution of methanesulfonic acid2-(6-benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-ethyl ester(1.12 g, 2.84 mmol) in thy DMF (25 mL) was stirred under argon at roomtemperature. Solid potassium iodide (0.25 g) and sodium azide (0.185 g,2.84 mmol) were added, and the reaction mixture was allowed to stir for48 hours. The reaction mixture was poured into 500 mL of water, and theaqueous mixture was extracted four times with 150 mL of EtOAc. Thecombined organic layers were washed with water, brine, dried (MgSO₄),and evaporated under reduced pressure to give an oil that was purifiedby eluting through silica gel with hexanes:EtOAc (3:2). After solventremoval, the resulting oil was dissolved in dry THF, cooled to 0° C.,and 5.68 mL of lithium aluminum hydride in THF (5.68 mmol) was addeddropwise via syringe to the stirring reaction mixture. The reactionmixture was allowed to warm to room temperature (about 30 minutes) andwas quenched by addition to 250 mL of water. The aqueous solution wasextracted twice with 250 mL of EtOAc, and the combined organic layerswere washed with water, brine, dried (MgSO₄), and evaporated underreduced pressure to give an oil. The oil was dissolved in MeOH, 2 mL of2M HCl in Et₂O) was added, and the solution was gently warmed, thencooled. The resulting residue was recrystallized from MeOH/Et₂O toafford 0.17 g (0.483 mmol, 17%) of2-(6-benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-ethylaminehydrochloride salt. MS: 316 (M+H)⁺.

Similarly prepared, using7-benzenesulfonyl-3,4-dihydro-2H-naphthalen-1-one,5-phenylsulfonyl-indan-1-one and6-(2-Fluoro-benzenesulfonyl)-3,4-dihydro-2H-naphthalen-1-onerespectively in step 1, were:

2-(7-Benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-ethylamine, MS:316 (M+H)⁺.

2-(5-Benzenesulfonyl-indan-1-yl)-ethylamine, MS: 302 (M+H)⁺; and

2-[6-(2-Fluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-ethylamine,MS: 334 (M+H)⁺.

Example 8N′-[2-(7-Benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-ethyl]-N,N-dimethyl-acetamidine

The synthetic procedure described in this Example was carried outaccording to the process shown in Scheme M.

2-(6-Benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-ethylamine (0.1g, 0.32 mmol) was added to 5 mL of dimethylformamide dimethyl acetal,and the reaction mixture was heated to 95° C. for two hours. Thereaction mixture was cooled and quenched by addition of 100 mL of water.The aqueous mixture was extracted twice with 150 mL of EtOAc, and thecombined organic layers were washed with water, brine, dried (MgSO₄),and evaporated under reduced pressure to give an oil. The crude oil wasdissolved in methylene chloride and eluted through silica gel with 1:1hexanes:EtOAc, after which solvent was removed under reduced pressure toyield 0.1 g (0.26 mmol, 81%) ofN′-[2-(7-Benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-ethyl]-N,N-dimethyl-acetamidine.MS: 386 (M+H)⁺.

Example 92-(6-Benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-ethyl]-dimethyl-amine

The synthetic procedure described in this Example was carried outaccording to the process shown in Scheme N.

Using the procedure described Journal of Organic Chemistry, 61(11),3849-3862 (1996), a solution of 0.680 g (2.16 mmol) of2-(6-benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-ethylamine andaqueous formaldehyde (0:439 mL of 37% solution, 5.40 mmol) in 35 mL of1,2-dichloroethane was stirred at room temperature for 10 minutes.NaBH(OAc)3 (2.75 g, 12.96 mmol) was added, and the reaction mixture wasstirred for 2 hours at room temperature. Saturated aqueous NaHCO₃ wasslowly added to quench the reaction, and the aqueous mixture wasextracted twice with 250 mL of EtOAc. The combined organic layers werewashed with water, brine, and dried (MgSO₄). Evaporation of the solventunder reduced pressured gave an oil that was eluted through a silica gelcolumn with hexanes/EtOAc (6:4:) to afford2-(6-benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-ethyl]-dimethyl-amine,which was recrystallized as an oxalate salt, 0.340 g (0.90 mmol, 41.6%).MS: 344 (M+H)⁺.

Example 103-(6-Benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-propylamine

The synthetic procedure described in this Example was carried outaccording to the process shown in Scheme O.

Step 13-(6-Benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-propionitrile

A solution of methanesulfonic acid2-(6-benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-ethyl ester(1.21 g, 3.07 mmol), potassium cyanide (0.799 g, 12.27 mmol) andpotassium iodide (0.25 g) in 50 mL of DMF was heated to 95° C. underargon with stirring for 24 hours. The reaction mixture was cooled andpoured into 500 mL of water. The aqueous mix was extracted three timeswith EtOAc, and the combined organic phases were washed with water,saturated brine, and dried (MgSO₄). Evaporation of the solvent underreduced pressure gave an oil that was purified by elution on silica gel(hexanes:EtOAc 1:1). Removal of the solvent under reduced pressureyielded 0.950 g (2.97 mmol, 95.1% of3-(6-benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-propionitrileas a white crystalline solid. MS: 326 (M+H)⁺.

Step 23-(6-Benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-propylamine

A solution of3-(6-benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-propionitrile(0.740 g, 2.27 mmol was dissolved in dry THF, and the reaction mixturewas stirred under argon at room temperature. BH₃ THF (6 mL) was addeddropwise, and the reaction mixture was allowed to stir for 15 hours. Thereaction mixture was quenched by careful addition of 10% aqueous HCl,followed by stirring for 10 minutes. The reaction mixture was placedunder reduced pressure to remove THF. The resulting aqueous solution wasdiluted with 10 mL of EtOH, made basic by addition of 0.5 M NaOHsolution, and warmed to 75° C. for 15 minutes. The solution was cooledand extracted three times with 150 mL of EtOAc. The combined organiclayers were washed with water, saturated brine, and dried (MgSO₄).Evaporation of the solvent under reduced pressure gave an oil that waspurified by elution on silica gel (MeOH:CHCl₃ 5:95). Removal of thesolvent yielded 0.190 g (0.577 mmol, 25.4%) of3-(6-benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-propylamine asan oil, which was recrystallized from EtOH/EtOAc as an oxalate salt(0.140 g, 0.334 mmol, 14.7% overall yield). MS: 330 (M+H)⁺

Example 113-(6-Benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-propionamidine

The synthetic procedure described in this Example was carried outaccording to the process shown in Scheme P.

3-(6-Benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-propionitrile(0.45 g, 1.4 mmol) was dissolved in a mixture of 15 mL EtOH and 10 mLCHCl₃, and the solution was sparged with nitrogen for two minutes, andthen with HCl gas for 15 minutes, after which the reaction mixture wasallowed to sit under HCl gas for 48 hours. The reaction mixture wasevaporated to dryness under reduced pressure, and the resulting residuewas dissolved in a mixture of 15 mL EtOH and 10 mL CHCl₃. This solutionwas added dropwise to 50 mL of ice cold solution of NH₃ (saturated) inMeOH. The solution was filtered to remove NH₄Cl, concentrated undervacuum, and dissolved in a mixture of CH₂Cl₂, EtOAc and MeOH (1:1:1).NH₄Cl was removed from this organic solution by filtration, and thesolvent was removed under reduced pressure to yield 0.32 g (0.94 mmol,67%) of3-(6-benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-propionamidineas an oil. MS: 343 (M+H)⁺.

Example 121-[2-(6-Benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-ethyl]-1H-imidazole

The synthetic procedure described in this Example was carried outaccording to the process shown in Scheme P.

Methanesulfonic acid2-(6-benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-ethyl ester(0.250 g, 0.634 mmol), imidazole (0.173 g, 2.54 mmol), potassiumcarbonate (0.175 g, 1.27 mmol) and potassium iodide (0.25 g) were addedto 50 mL of acetonitrile, and the reaction mixture was refluxed for 16hours under argon. The reaction mixture was cooled and poured into 300mL of water, extracted twice with 250 mL of EtOAc, and the combinedorganic layers were washed with water, saturated brine, and dried(MgSO₄). The solvent was removed under reduced pressure to yield an oilthat was purified via silica gel column, eluting with MeOH/CHCl₃ (5:95).Solvent was removed under reduced pressure to afford 0.180 g (0.491mmol, 77.5% of1-[2-(6-benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-ethyl]-1H-imidazoleas an oil. The oil was recrystallized from EtOH/HCl to give 0.130 g ofthe corresponding hydrochloride salt (0.323 mol, 50.9%). MS: 367 (M+H)⁺.

Example 13S-(6-Benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl)-methylamine

The synthetic procedure described in this Example was carried outaccording to the process shown in Scheme Q.

Step 1 R-6-Phenylsulfanyl-1,2,3,4-tetrahydro-naphthalen-1-ol

This step follows the general procedure of Salunkhe and Burkhardt,Tetrahedron Letters 38(9): 1523 (1997). A solution of 1.4 mL (1.4 mmole)1.0M S-2-methyl-CBS-oxazaborolidine in toluene and 2.8 mL (15.8 mmole)borane-diethylaniline complex in 15 mL toluene was heated at 30° C.under a dry nitrogen atmosphere. A solution of 3.5 g (13.8 mmole)6-phenylsulfanyl-3,4-dihydro-2H-naphthalene-1-one in 15 mL toluene wasadded dropwise over 2 hours. The reaction mixture was stirred at 30-32°C. for one hour. Methanol (5.0 mL) was added dropwise over 20 minutesfollowed by 10 mL 1.0N hydrochloric acid. The mixture was stirred for 20minutes, then it was diluted with 50 mL ethyl ether. The organic phasewas washed twice with 25 mL water, once with 20 mL saturated sodiumchloride, dried (magnesium sulfate) and concentrated under reducedpressure. The residue was recrystallized from ether/hexane to giveR-6-phenylsulfanyl-1,2,3,4-tetrahydro-naphthalen-1-ol, 3.49 g (98%),m.p. 74-75° C. M+H=256; [α]_(D)=−30.8° (c=1, CHCl₃). Chiral HPLC on aChiracel OD (20 microns) eluting with 5% isopropyl alcohol in hexane,retention time=10.9 min, 99.9 ee.

Step 2S-2-Ethoxycarbonyl-2-(6-phenylsulfanyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-malonicacid diethyl ester

This step follows the general procedure of Hillier, et al, OrganicLetters 6(4): 573 (2004). A solution of 3.3 g (12.9 mmole)R-6-phenylsulfanyl-1,2,3,4-tetrahydro-naphthalen-1-ol, 5.97 g (25.7mmole) triethylmethane tricarboxylate and 2.3 mL (25.7 mmole) 97%trimethylphosphine in 60 mL toluene under nitrogen was cooled to −55° C.Neat diisopropylazodicarboxylate (5.06 mL, 25.7 mmole) was addeddropwise over 30 minutes. The reaction mixture was stirred at −55° C.for ½ hour, then allowed to warm to 22° over 2 hours and then stirred at22° C. for 1 hour. The solution was concentrated under reduced pressure.To the residue was added 50 mL 3N sodium hydroxide. The mixture wasextracted with 200 mL diethyl ether. The organic phase was washed twicewith 25 mL 3 N sodium hydroxide, once with 25 mL water, twice with 25 mL1 N hydrochloric acid, once with 25 mL saturated sodium chloride, dried(magnesium sulfate), and concentrated under reduced pressure. Theresidue was triturated with 50 mL 50% ethyl ether/hexane. Theprecipitated diisopropylhydrazine dicarboxylic acid was removed byfiltration. The filtrate was concentrated and the residue was subjectedto low pressure column chromatography over silica gel 230-400 mesheluting with 10% ethyl acetate in hexane. The product was obtained as asolid, 3.71 g (61%) which was determined by chiral HPLC (Chiralpak OJ,10% isopropanol in hexane, retention time=10.5 minutes) to be 90 ee. Ananalytical sample obtained by recrystallization from ethyl ether/hexanehad m.p. 85-86° C., M+H=470, [α]_(D)=+30.2° (c=1.0, CHCl₃), and wasdetermined to be 98.8 ee by chiral HPLC analysis.

Step 3 R-(6-Phenylsulfanyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-aceticacid

To a solution of 0.6 g (1.3 mmole) 90 eeS-2-ethoxycarbonyl-2-(6-phenylsulfanyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-malonicacid diethyl ester in 10 mL methanol and 2 mL water was added 2.6 mL 3 Nsodium hydroxide. The reaction mixture was heated under reflux for 18hours. The mixture was concentrated under reduced pressure, and theresidue was dissolved in 10 mL glacial acetic acid. The solution washeated under reflux for 4 hours and then it was concentrated underreduced pressure. The residue was partitioned between 20 mL 0.1 Nhydrochloric acid and 30 mL ethyl acetate. The organic phase was washedwith 10 mL water, 10 mL saturated sodium chloride, dried (magnesiumsulfate) and concentrated under reduced pressure to yieldR-(6-phenylsulfanyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-acetic acid asan oil, 0.38 g (98%), M+H=299. A sample of this acid was converted tothe methyl ester using trimethylsilyl diazomethane. Chiral HPLC onChiralpak OJ, 10% isopropyl alcohol/hexane, showed 90 ee.

Step 4S-Methyl-(6-phenylsulfanyl-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl)-carbamicacid tert-butyl ester

To a solution of 0.38 g (1.27 mmole) 90 eeR-(6-phenylsulfanyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-acetic acid in 6mL methylene chloride was added 2 drops DMF and 0.22 mL (2.55 mmole)oxalyl chloride. The solution was stirred at 23° C. for 30 minutes andthen concentrated under reduced pressure. The residue was dissolved in 6mL acetone and cooled to 0° C. in an ice bath. A solution of 0.206 g(3.18 mmole) sodium azide in 2 mL water was added dropwise, and thereaction mixture was stirred from 0° C. to 22° C. over 30 minutes. Themixture was diluted with 20 mL water, 25 mL saturated sodium chloridewas added, and the mixture was extracted with 50 mL toluene. The organicphase was dried (magnesium sulfate) and then heated under reflux for 30minutes. The solution was concentrated under reduced pressure and theresidue was dissolved in 10 mL tetrahydrofuran. The resulting solutionwas added dropwise to a solution of 2.5 mL 0.2 M lithium aluminumhydride in tetrahydrofuran. The reaction mixture was stirred at 23° C.for 30 minutes, then at reflux for 20 minutes. Water was added dropwiseuntil gas evolution ceased. The mixture was filtered and concentratedunder reduced pressure, and the residue was partitioned between 20 mL 6N hydrochloric acid and 25 mL ethyl ether. The aqueous phase was cooledin an ice bath and made strongly basic with solid sodium hydroxidepellets. The mixture was extracted with 35 mL ethyl ether, and theorganic phase was dried (magnesium sulfate) and concentrated underreduced pressure. The residue was dissolved in 10 mL tetrahydrofuran anda solution of 0.12 g (0.54 mmole) di-tert-butyl dicarbonate in 2 mLtetrahydrofuran was added. The reaction mixture was stirred at 23° C.for 30 minutes and then concentrated under reduced pressure. The residuewas subjected to low pressure column chromatography over silica gel230-400 mesh eluting with 5% ethyl acetate in hexane.S-Methyl-(6-phenylsulfanyl-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl)-carbamicacid tert-butyl ester was obtained as an oil, 0.13 g (27%) M+H=384.

Step 5S-(6-Benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl)-methyl-carbamicacid tert-butyl ester

To a solution of 0.13 g (0.34 mmole)S-methyl-(6-phenylsulfanyl-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl)-carbamicacid tert-butyl ester in 5 mL methylene chloride was added 0.175 g (1.02mmole) meta-chloroperbenzoic acid. The reaction mixture was stirred at23° C. for 30 minutes. The solution was concentrated under reducedpressure and the residue was dissolved in 25 mL ethyl ether. Thesolution was washed twice with 5 mL 5% sodium hydroxide and 15 mL water.The organic phase was dried (magnesium sulfate) and concentrated underreduced pressure to giveS-(6-benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl)-methyl-carbamicacid tert-butyl esteras a white foam, 0.1 g (71%), M+H=416. Chiral HPLC(Chiralpak AS, 25% isopropyl alcohol in hexane) retention time=16.9minutes, 90 ee.

Step 6S-(6-Benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl)-methylaminetrifluoroacetate salt

To a solution of 0.1 g (0.24 mmole) 90 eeS-(6-benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl)-methyl-carbamicacid tert-butyl ester in 1.0 mL methylene chloride was added 1.0 mLtrifluoroacetic acid. The mixture was stirred at 23° C. for 15 minutes.The solution was concentrated under reduced pressure and the residue wasrecrystallized from ethyl acetate/ethyl ether to provideS-(6-benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl)-methylamineas a trifluoroacetate salt, 0.093 g (90%), m.p. 146-147° C., M+H=316,[α]_(D)=+0.4° (c=1.0, methanol).

Example 14R-(6-Benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl)-methylamine

The synthetic procedure described in this Example was carried outaccording to the process shown in Scheme S.

Step 1 Trifluoro-methanesulfonic acid5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yl ester

6-Hydroxytetralone (12 g, 0.072 mole) and triethylamine (10 mL, 0.072mole) were dissolved in 200 ml methylene chloride and cooled in an icebath. Trifluormethanesulfonic anhydride (20 g, 0.072 mole) was addeddropwise, and the reaction mixture was stirred for 30 minutes. Thereaction mixture was poured into 200 mL water, and the organic layer wasseparated and dried over magnesium sulfate. Evaporation of solvent underreduced pressure gave 15.5 g of trifluoro-methanesulfonic acid5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yl ester as an oil. MS: 295 (M+H)⁺

Step 2 6-Benzenesulfonyl-3,4-dihydro-2H-naphthalen-1-one

Trifluoro-methanesulfonic acid 5-oxo-5,6,7,8-tetrahydro-naphthalen-2-ylester (13.0 g, 0.044 mole), sodium benzenesulfinate (7.25 g, 0.044mole), 4,5-bis(diphenylphosphino, -9,9-dimethyl Xanthos (1.1 g,0.004mole), tris(dibenzylideneacetone) dipalladium(0) (1.0 g, 0.004mole), cesium carbonate (5.0 g) and tetrabutylammonium fluoride (5 mL of1M in THF) were all added to 100 mL toluene, and the reaction mixturewas refluxed for four hours. The reaction mixture was cooled to roomtemperature and partitioned between ethyl acetate and water. The organiclayer was dried over magnesium sulfate, and solvent was removed underreduced pressure. The resulting residue was purified by medium pressurechromatography eluting with methylene chloride to yield 5.5 g of6-benzenesulfonyl-3,4-dihydro-2H-naphthalen-1-one. Mp: 121° C. MS: 287(M+H)⁺.

Step 3 S-6-Benzenesulfaoyl-1,2,3,4-tetrahydro-naphthalen-1-ol

This step follows the general procedure of Salunkhe and Burkhardt,Tetrahedron Letters 38(9): 1523 (1997). A solution of R-2-methyl CBSoxaborilidine (2.2 mL, (0.002 mole, 1M in toluene) anddiethylanaline-borane complex (4.6 mL, 0.026 mole) in 200 mL toluene washeated to 35° C. 6-Benzenesulfonyl-3,4-dihydro-2H-naphthalen-1-one (6.5g, 0.022 mole) in 100 mL toluene was added dropwise over two hours. Thereaction was quenched with 20 mL of 10% HCl followed by 30 mL methanol,and the reaction mixture was stirred for 30 minutes. The reactionmixture was diluted with 200 mL water, extracted with ethyl acetate, anddried over magnesium sulfate. Solvent was evaporated under reducedpressure, and the residue was recrystallized from toluene/MTBE to yield6 g of S-6-phenylsulfanyl-1,2,3,4-tetrahydro-naphthalen-1-ol. Mp: 136°C. MS: 288 (M+H)⁺. 99%+ee anlysis by chiral HPLC Chiralpak AD, elutingwith 5% IPA in hexane, retention time=29.7minutes.

Step 4R-2-(6-Benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-2-ethoxycarbonyl-malonicacid diethyl ester

S-6-Phenylsulfanyl-1,2,3,4-tetrahydro-naphthalen-1-ol (2.0 g, 6.9mmole),trimethylphosphine (13.9 mL, 13.9 mmol, 1M in THF), andtriethylmethylenetricarboxylate (2.9 mL, 13.9 mmol) were dissolvedtogether in 75 mL toluene, and the temperature of the reaction mixturewas lowered to −50° C. A solution of di-t-butylazidodicarboxylate (3.2g, 13.9 mmol) in 15 mL THF was added dropwise over 25 minutes, and thereaction mixture was stirred at −50° C. for an additional 30 minutes.The reaction mixture was allowed to warm to 25° C., and stirring wascontinued for three hours. The reaction mixture was partitioned betweenwater and ethyl acetate, and the organic phase was dried over magnesiumsulfate. Solvent was removed under reduced pressure, and the residue waspurified by medium pressure chromatography, eluting with 25%ethylacetate in hexane to give 1.3g ofR-2-ethoxycarbonyl-2-(6-phenylsulfanyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-malonicacid diethyl ester. MS: 504 (M+H)⁺.

Step 5 S-(6-Benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-aceticacid ethyl ester

R-2-ethoxycarbonyl-2-(6-phenylsulfanyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-malonicacid diethyl ester 1.3 g, 2.6 mmol), lithium chloride (0.33 g, 7.8 mmol)and 0.2 mL water were added to 20 mL of dimethyl sulfoxide. The reactionmixture was refluxed for two hours and then cooled to room temperature.The reaction mixture was diluted with 40 mL of water, and extracted withethyl acetate. The organic layer was dried over magnesium sulfate, andsolvent was removed under reduced pressure to yield 0.8 g ofS-(6-benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-acetic acidethyl ester as an oil. MS: 359 (M+H)⁺. 96% ee by chiral HPLC, chiralpakAD eluting with 20% IPA in hexane, retention time 12.2 minutes.

Step 6 (6-Benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-aceticacid

S-(6-Benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-acetic acidethyl ester (0.8 g, 2.23 mmol) and 10mL of 10% NaOH were added tp 20 mLethanol, and the reaction mixture was refluxed for 30 minutes. Thereaction mixture was diluted with 100 mL of water and acidified with 10%HCl. The aqueous mixture was extracted with ethyl acetate, and theorganic layer was dried over magnesium sulfate. Solvent was removedunder reduced pressure, and the residue was recrystallized from MTBE togive 0.4 g of(6-benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-acetic acid. MS:331 (M+H)⁺. Mp: 144° C.

Step 7R-(6-Benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl)-methylamine

(6-Benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-acetic acid (0.3g, 1.0 mmol) and triethylamine (0.15 mL, 1.1 mmol) were dissolved in 15mL acetone, and the reaction mixture was cooled in an ice-bath. n-Butylchloroformate (0.15 mL, 1.1 mmol) was added dropwise over five minutesto the stirring reaction mixture. After stirring an additional 220minutes, sodium azide (0.13 g, 2.1 mmol) in 5 mL water was addeddropwise. The reaction mixture was stirred another 20 minutes at icebath temperature. The reaction was quenched by addition of 50 mL waterand the resulting aqueous mixture was extracted with 70 mL toluene. Thetoluene solution was dried over magnesium sulfate and filtered. Thetoluene solution was then heated to reflux for 30 minutes, cooled toroom temperature, and solvent was removed under reduced pressure. Theresulting residue was dissolved in a mixture of 10 mL THF and 30 mLdiethyl ether, and cooled in an ice-bath. Lithium aluminum hydride (3 mLof 1M in ether) was added dropwise, and the suspension stirred at icebath temperature for three hours. The reaction was quenched with 3 mL10% NaOH, and sodium sulfate drying agent was added. The organicsolution was recovered by filtration and solvent was removed underreduced pressure to yield and the mixture filtered after 30 min. Theorganic solution is evaporated to giveR-(6-benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl)-methylamineas an oil. MS: 316 (M+H)⁺.

Example 15R-[6-(3-Methoxy-benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1ylmethyl]methyl-amine

The synthetic procedure described in this Example was carried outaccording to the process shown in Scheme T.

Step 1 6-Iodo-3,4-dihydro-2H-naphthalen-1-one

A mixture of N-(5-oxo-5,6,7,8-tetrahydronaphthalen-2-yl)-acetamide 2.5grams (12.3 mmole) in 20 mL 20% sulfuric acid was heated at 90° for 45minutes. The solution was allowed to cool to room temperature whereupon6-amino-3,4-dihydro-2H-naphthalen-1-one sulfate (not shown) precipitatedas a solid mass. To this solid was added 20 mL water and 20 mL glacialacetic acid. The resulting solution was stirred in an ice bath and asolution of 1.72 grams (25 mmoles) sodium nitrite in 15 mL water wasadded dropwise over 0.5 hour. The reaction mixture was slowly pouredinto a well stirred solution of 8 grams (48 mmoles) potassium iodide in80 mL water. The mixture was extracted with 200 mL ethyl ether, and theorganic phase was washed with water, then saturated sodium hydrogensulfite, then with saturated sodium chloride. The organic phase wasdried (magnesium sulfate) and concentrated under reduced pressure. Theresidue was subjected to low pressure column chromatography over silicagel 230-400 mesh eluting with 5% ethyl acetate in hexane.6-Iodo-3,4-dihydro-2H-naphthalen-1-one was obtained as a white solid,3.12 grams (94%), m.p. 77-78°.

Step 2 S-6-Iodo-1,2,3,4-tetrahydro-naphthalen-1-ol

A solution of R-2-methyl-CBS-oxazaborolidine (MCBSOB, 3.7 mL (3.7mmoles) 1.0 M in toluene) and borane-diethylaniline complex (BDEA, 7.5mL, 42 mmoles) in 40 mL toluene was heated to 30°. A solution of6-iodo-3,4-dihydro-2H-naphthalen-1-one (10 grams, 36.8 mmoles) in 40 mLtoluene was added dropwise over 2.5 hours. The reaction mixture wasstirred for an additional 0.5 hour at 30°. To the solution (at roomtemperature) was added 20 mL methanol. After 0.25 hour, 50 mL 1Nhydrochloric acid was added slowly. The mixture was stirred for 20minutes then it was extracted with 200 mL ethyl ether. The organic phasewas washed with 1N hydrochloric acid, water, and saturated sodiumchloride. The organic phase was dried (magnesium sulfate) andconcentrated under reduced pressure. To the oily residue was added 100mL hot hexane. When crystallization was complete, the white solid wascollection and dried to giveS-6-iodo-1,2,3,4-tetrahydro-naphthalen-1-ol, 9.62 grams (95%). m.p.102-103°, M⁺=274, [α]_(D)=+12.2° (c=1, chloroform).

Step 3R-2-Ethoxycarbonyl-2-(6-iodo-1,2,3,4-tetrahydro-naphthalen-1-yl)-malonicacid diethyl ester

To a solution of S-6-iodo-1,2,3,4-tetrahydro-naphthalen-1-ol (9.5 grams,34.7 mmoles) and triethylmethane tricarboxylate (TEMTC, 16 grams, 69.3mmoles) in 150 mL toluene was added 70 mL 1.0M trimethylphosphine intoluene. The solution was stirred and cooled to −50° under nitrogen.Neat diisopropylazodicarboxylate (DIADC, 14 mL, 69.3 mmoles) was addeddropwise over 0.5 hour. The solution was concentrated under reducedpressure. To the residue was added 100 mL water and 100 mL 3N sodiumhydroxide. The mixture was extracted with diethyl ether, and the organicphase was washed with 3N sodium hydroxide, water, 1N hydrochloric acid,water again, then saturated sodium chloride. After drying (magnesiumsulfate), the solution was concentrated under reduced pressure. To theresidue was added 25 mL diethyl ether. After 10 minutes the crystallinedeposit of diisopropyl-1,2-hydrazinedicarboxylate was removed byfiltration. The filtrate was concentrated under reduced pressure and theresidue was subjected to low pressure column chromatography over 230-400mesh silica gel eluting with 7% ethyl acetate in hexane.R-2-Ethoxycarbonyl-2-(6-iodo-1,2,3,4-tetrahydro-naphthalen-1-yl)-malonicacid diethyl ester was obtained as a white crystalline solid (fromhexane), 14.84 grams (88%), m.p. 86-87°, [α]_(D)=−20.3°(c=1,chloroform), M⁺=488.

Step 4 S-6-Iodo-1,2,3,4-tetrahydro-naphthalen-1-yl acetic acid

To a solution ofR-2-ethoxycarbonyl-2-(6-iodo-1,2,3,4-tetrahydro-naphthalen-1-yl)-malonicacid diethyl ester (14 grams, 28.7 mmoles) in 25 mL methanol was added60 mL water and 60 mL 3N sodium hydroxide. The reaction mixture washeated under reflux for 20 hours, then concentrated under reducedpressure. To the residue was added 200 mL glacial acetic acid. Thesolution was heated under reflux for 3 hours, and then it wasconcentrated under reduced pressure. The residue was partitioned between60 mL water and 300 mL ethyl ether. The organic phase was dried(magnesium sulfate) and concentrated under reduced pressure. The residuewas recrystallized from ethyl ether/hexane to giveS-6-iodo-1,2,3,4-tetrahydro-naphthalen-1-yl acetic acid, 7.6 grams(84%), m.p. 90-91°, M⁺=316, [α]_(D)=+20 (c=1, chloroform).

Step 5 R—C-(6-Iodo-1,2,3,4-tetrahydro-naphthlen-1-yl)-methylaminehydrochloride

To a solution of S-6-iodo-1,2,3,4-tetrahydro-naphthalen-1-yl acetic acid(28.4 grams, 90 mmoles) in 350 mL dichloromethane was added 5 drops DMFand 12 mL (0.135 mole) oxalyl chloride. The reaction mixture was stirredat 23° for 1 hour and then it was concentrated under reduced pressure.The residue was dissolved in 250 mL acetone and the solution was cooledto 0°. A solution of sodium nitrite (12 grams, 0.18 mole) in 80 mL waterwas added dropwise over 0.5 hour. The reaction mixture was diluted with400 mL water and 200 mL saturated sodium chloride. The mixture wasextracted with 500 mL toluene, and the organic phase was dried(magnesium sulfate), then heated under reflux for 0.5 hour. The solutionwas concentrated under reduced pressure. The residue was dissolved in150 mL dioxane and the solution was added dropwise to a boiling solutionof 250 mL concentrated hydrochloric acid over 40 minutes. The solutionwas decanted from a small amount of tar and the warm decantate wasconcentrated under reduced pressure. The residue was recrystallized fromethanol/ethyl ether to provideR—C-(6-iodo-1,2,3,4-tetrahydro-naphthlen-1-yl)-methylamine hydrochlorideas the hydrochloride salt, 23.3 grams (80%), m.p. 276-277°, M⁺=287,[α]_(D)=−2.8° (c=1, methanol).

Step 6 R-(6-Iodo-1,2,3,4-tetrahydro-naphthlen-1-ylmethyl)-carbamic acidtert-butyl ester

To a stirred mixture ofR—C-(6-iodo-1,2,3,4-tetrahydro-naphthlen-1-yl)-methylamine hydrochloride(15 grams, 46.4 mmoles) and 8 mL triethylamine in 250 mL THF was addeddropwise a solution of di-tert-butyl dicarbonate (10.9 grams, 49.9mmoles) in 50 mL THF. The reaction mixture was stirred at 23° for 2hours, then was concentrated under reduced pressure. The residue waspartitioned between 300 mL ethyl ether and 150 mL water. The organicphase was dried (magnesium sulfate) and concentrated under reducedpressure. The residue was recrystallized from diethyl ether/hexane toprovide R-(6-iodo-1,2,3,4-tetrahydro-naphthlen-1-ylmethyl)-carbamic acidtert-butyl ester, 12.91 grams (72%), m.p. 121-122°, M⁺=387, [α]_(D)=+24°(c=1, chloroform).

Step 7R-[6-(3-Methoxy-phensulfanyl)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-carbamicacid tert-butyl ester

This step follows the general procedure of Itoh and Mase, OrganicLetters 6(24): 4587 (2004). In 15 mL dioxane was mixedR-(6-iodo-1,2,3,4-tetrahydro-naphthlen-1-ylmethyl)-carbamic acidtert-butyl ester (0.5 gram, 1.29 mmoles),tris(dibenzylideneacetone)dipalladium(0) (0.059 gram, 0.064 mmoles),4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.074 gram, 0.128mmoles), diisopropylethyl amine (0.333 gram, 2.58 mmoles) and3-methoxy-thiophenol (0.2 gram, 1.42 mmoles). The reaction mixture wasstirred at 50° for 1 hour, then was diluted with 50 mL diethyl ether andfiltered. The filtrate was washed with 10 mL water, dried (magnesiumsulfate) and concentrated under reduced pressure. The residue wassubjected to low pressure column chromatography over silica gel 230-400mesh eluting with 10% ethyl acetate in hexane. The eluted product wasrecrystallized from hexane to provideR-[6-(3-Methoxy-phensulfanyl)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-carbamicacid tert-butyl ester, 0.46 gram (89%), m.p. 73-74° C., M⁺=399,[α]_(D)=+26.6° (c=1, chloroform).

Step 8R-[6-(3-Methoxy-benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-carbamicacid tert-butyl ester

To a solution ofR-[6-(3-methoxy-phensulfanyl)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-carbamicacid tert-butyl ester (0.2 gram, 0.5 mmole) in 10 mL dichloromethane wasadded m-chloroperbenzoic acid (0.3 gram, 1.34 mmole of 77% solids). Thereaction mixture was stirred at 23° for 0.5 hour. The solution wasconcentrated under reduced pressure and the residue was partitionedbetween 50 mL ethyl acetate and 30 mL 5% sodium hydroxide. The organicphase was washed with saturated sodium chloride, dried (magnesiumsulfate) and concentrated under reduced pressure to giveR-[6-(3-methoxy-benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-carbamicacid tert-butyl ester, 0.21 gram (97%), M⁺Na=454.

Step 9R-[6-(3-Methoxy-benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-methyl-carbamicacid tert-butyl ester

To a solution ofR-[6-(3-methoxy-benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-carbamicacid tert-butyl ester (0.2 gram, 0.46 mmole) in 3 mL DMF was added 0.025gram (1 mmole) of 100% sodium hydride. To this mixture was addediodomethane (0.1 mL, 1.6 mmole). The reaction mixture was stirred at 23°for 2 hours, then was diluted with 25 mL water and extracted with 40 mLethyl acetate. The organic phase was washed with water and saturatedsodium chloride, dried (magnesium sulfate) and concentrated underreduced pressure. The residue was subjected to low pressure columnchromatography over silica gel 230-400 mesh eluting with 20% ethylacetate in hexane.R-[6-(3-Methoxy-benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-methyl-carbamicacid tert-butyl ester was obtained as a foam, 0.15 gram (73%), M⁺=445,[α]_(D)=+16.4° (c=1, methanol).

Step 10,R-[6-(3-Methoxy-benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1ylmethyl]-methyl-amine

A warm solution ofR-[6-(3-methoxy-benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-methyl-carbamicacid tert-butyl ester (0.12 gram, 0.27 mmole) in 2 mL TFA wasconcentrated under reduced pressure. To the residue was added 0.5 mLmethanol and 1.0 mL 1N hydrochloric acid in ethyl ether. The mixture washeated to boiling for 30 seconds and then it was concentrated underreduced pressure.R-[6-(3-Methoxy-benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1ylmethyl]-methyl-aminehydrochloride was obtained by recrystallization from methanol/ethylacetate/ethyl ether, 0.08 gram (78%), m.p. 194-195°, M⁺H=346,[α]_(D)=−3.4° (c=1, methanol).

Similarly prepared using the procedure of Example 15 were:

R—C-[6-(-3-Methoxy-benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-methylaminehydrochloride: m.p. 188-189° C., M⁺H=332, [α]_(D)=−6.0° (c=1, methanol);

R—C-[6-(3-Methanesulfonyl-benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-methylaminehydrochloride; m.p. 265-266° C., M⁺H=380;

R—C-[6-(1H-Pyrazole-4-sulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-methylamine;m.p. 181-182° C., M⁺H=292;

R—C-[6-(1-Methyl-1H-imidazole-2-sulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-methylamineoxalate: m.p. 196-197° C., M⁺H=306;

R—C-[6-(3H-Indole-3-sulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-methylamine,M⁺H=341;

R—C-[6-(5-Fluoro-3H-indole-3-sulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-methylamine,M⁺H=359;

R—C-[6-(1H-Pyrrole-3-sulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-methylamine,M⁺H=291.

R-Methyl-[6-(1H-pyrrole-3-sulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-aminehydrochloride, M⁺H=305;

R—C-[6-(6-Fluoro-3H-benzimidazole-4-sulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-methylamineoxalate, M⁺H=360;

R—C-(6-Benzenesulfonyl-8-fluoro-1,2,3,4-tetrahydro-naphthalen-1-yl)-methylaminehydrochloride, m.p. 248-249° C., M⁺H=320, [α]_(D)=+25.2° (c=1,methanol);

R-(6-Benzenesulfonyl-8-fluoro-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl)-methyl-aminehydrochloride, M⁺H=334, [α]_(D)=+18.5° (c=1, methanol);

R—C-(6-Benzenesulfonyl-5-fluoro-1,2,3,4-tetrahydro-naphthalen-1-yl)-methylaminehydrochloride, M⁺H=320, [α]_(D)=+11.2° (c=0.5, methanol);

[6-(3-Fluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-methyl-amineoxalate, M⁺H=334; and

Ethyl-[6-(3-fluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-amineoxalate, M⁺H=348.

Example 16R-3-(5-Aminomethyl-5,6,7,8-tetrahydro-naphthalene-2-sulfonyl)-benzonitrile

The synthetic procedure described in this Example was carried outaccording to the process shown in Scheme U.

Step 1R-[6-(3-Cyano-benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-carbamicacid tert-butyl ester

The sodium 3-cyanobenzenesulfinate used in this step was prepared byheating a solution of sodium sulfite (3.2 grams, 25.2 mmoles) in 10 mLwater to 80°, and adding dropwise thereto a solution of3-cyanobenzenesulfonyl chloride (2.55 grams, 12.6 mmoles) in 7 mL THFand a solution of sodium bicarbonate (2.1 grams, 25.2 mmoles). Themixture was extracted with -diethyl ether and the aqueous phase wasconcentrated under reduced pressure, heated, and filtered throughWhatman GF/B glass fiber filter. The filtrate was concentrated underreduced pressure to give 1.92 grams (81%), of sodium3-cyanobenzenesulfinate m.p. 216-218° C.

Following the general procedure of Cacchi et al., J. Organic Chemistry:69(17): 5608-5614 (2004), a mixture ofR-(6-iodo-1,2,3,4-tetrahydro-naphthlen-1-ylmethyl)-carbamic acidtert-butyl ester (0.4 gram, 1.0 mmole) sodium 3-cyanobenzenesulfinicacid (0.246 gram, 1.3 mmole), tris(dibenzylideneacetone)dipalladium(0)(0.05 gram, 0.054 mmole),4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.062 gram, 0.108mmole), cesium carbonate (0.53 gram, 1.5 mmole), and tetra-n-butylammonium chloride (0.362 gram, 1.3 mmole) in 10 mL toluene was heated at95° for 4 hours. The reaction mixture was diluted with 80 mL ethylacetate and washed with saturated sodium chloride. The organic phase wasdried (magnesium sulfate) and concentrated under reduced pressure. Theresidue was subjected to low pressure column chromatography over silicagel 230-400 mesh eluting with 25% ethyl acetate in hexane.R-[6-(3-Cyano-benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-carbamicacid tert-butyl ester was obtained as a foam, 0.2 gram (47%), M⁺=426,[α]_(D)=+5° (c=1, methanol).

Step 2R-3-(5-Aminomethyl-5,6,7,8-tetrahydro-naphthalene-2-sulfonyl)-benzonitrile

Following the procedure of steps 9 and 10 of Example 15,R-3-(5-Aminomethyl-5,6,7,8-tetrahydro-naphthalene-2-sulfonyl)-benzonitrilewas prepared as an oxalate salt: m.p. 212-213° C., M⁺H=327,[α]_(D)=+5.8° (c=1, DMSO);

Example 17R—N-(6-Benzenesulfonyl-8-fluoro-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl)-acetamide

The synthetic procedure described in this Example was carried outaccording to the process shown in Scheme V.

Step 1 6,8-Difluoro-3,4-dihydro-2H-naphthalen-1-one

This step follows the general procedure reported by Eaton et al.,Organic Chemistry 38(23): 4071-4073 (1973). Eaton's reagent, preparedfrom 32 g phosphorus pentoxide and 192 mL methanesulfonic acid, washeated at 65° C. A solution of 4-(3,5-difluoro-phenyl)-butyric acid(12.85 grams, 64.19 mmoles, prepared as described by Repke et al., U.S.Pat. No. 5,538,988) in 30 mL methanesulfonic acid was added and thereaction mixture was heated at 65° C. for 35 minutes. The mixture waspoured onto 1 L cracked ice and the product was extracted twice with 500mL of a mixture of 2 parts diethyl ether to 1 part ethyl acetate. Theorganic phase was washed with saturated sodium bicarbonate, water,saturated sodium chloride and then it was dried (magnesium sulfate). Thesolution was concentrated under reduced pressure.6,8-Difluoro-3,4-dihydro-2H-naphthalen-1-one was isolated byrecrystallization from hexane, 9.55 grams (82%), m.p. 57-58° C.

Step 2 8-Fluoro-6-phenylsulfanyl-3,4-dihydro-2H-naphthalen-1-one

A mixture of 6,8-difluoro-3,4-dihydro-2H-naphthalen-1-one (1.0 gram, 5.5moles) and potassium thiophenolate (0.81 gram, 5.5 mmole) in 4 mL DMSOwas heated at 50° C. for 0.5 hour. The mixture was diluted with 30 mL0.1N hydrochloric acid and then it was extracted with 50 mL diethylether. The organic phase was washed with water, dried (magnesiumsulfate) and concentrated under reduced pressure.8-Fluoro-6-phenylsulfanyl-3,4-dihydro-2H-naphthalen-1-one was obtainedby recrystallization of the residue from ethyl acetate/hexane, 0.871gram (58%), m.p. 112-113° C., M⁺H=273.

Step 3R-(6-benzenesulfonyl-8-fluoro-1,23,4-tetrahydro-naphthalen-1-ylmethyl)-carbamicacid tert-butyl ester

R-(6-benzenesulfonyl-8-fluoro-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl)-carbamicacid tert-butyl ester was obtained by preparing(8-fluoro-6-phenylsulfanyl-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl)-carbamicacid tert-butyl ester (not shown) by the procedure of steps 2 through 6of Example 15 above, then oxidizing the sulfanyl compound to thesulfonyl product using the procedure of step 8 of Example 15. M⁺H=420.

Step 4R—N-(6-Benzenesulfonyl-8-fluoro-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl)-acetamide

A warm solution ofR-(6-benzenesulfonyl-8-fluoro-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl)-carbamicacid tert-butyl ester (0.1 gram, 0.24 mmole) in 2 mL TFA wasconcentrated under reduced pressure. The residue was dissolved in 5 mLpyridine, and 0.5 mL acetic anhydride was added. The reaction mixturewas stirred at 23° for 2 hours. The solution was concentrated underreduced pressure and the residue was partitioned between 25 mLchloroform and 5 mL water. The organic phase was dried (magnesiumsulfate) and concentrated under reduced pressure to leaveR—N-(6-benzenesulfonyl-8-fluoro-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl)-acetamideasa homogenous foam, 0.06 gram (69%), M⁺H=362.

Similarly prepared wasR—N-[6-(1H-Indole-3-sulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-acetamide,N+H=383.

Example 18R-2-{[6-(3-Fluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-amino}-3,5-dihydro-imidazol-4-one

The synthetic procedure described in this Example was carried outaccording to the process shown in Scheme W.

A mixture ofR—C-[6-Fluoro-benzenesulfonyl]-1,2,3,4-tetrahydro-naphthalen-1-yl]-methylamine(0.28 grams, 0.877 mmole), 2-methylsulfanyl-3,5-dihydro-imidazol-4-one(0.25 grams, 0.96 mmole, prepared by the method reported by Chen et al.,WO9736859) and sodium hydroxide (0.038 grams, 0.96 mmole) in 6 mLethanol was heated under reflux for 22 hours. The solution wasconcentrated under reduced pressure to 1/3 volume, diluted with 25 mLethyl acetate, and washed with 10 mL 5% sodium carbonate. The organicphase was dried (magnesium sulfate) and concentrated under reducedpressure. The residue was subjected to column chromatography over silicagel 230-400 mesh eluting with a gradient of 2-15% methanol in chloroformcontaining 0.25% ammonium hydroxide.R-2-{[6-(3-Fluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-amino)-3,5-dihydro-imidazol-4-onewas obtained as a white solid, 0.205 grams (58%), M⁺H=402.

Example 19C-[6-(6-Fluoro-1H-benzoimizol-4-ylsulfanyl)-1.2,3,4-tetrahydro-naphthalen-1-yl]-methylamine

The synthetic procedure described in this Example was carried outaccording to the process shown in Scheme X.

Step 1 R-Thioacetic acidS-[5-(tert-butoxycarbonylamino-methyl)-5,6,7,8-tetrahydro-naphthalen-2-yl]ester

A mixture of R-(6-iodo-1,2,3,4-etrahydro-naphthlen-1-ylmethyl)-carbamicacid tert-butyl ester (2.0 grams,5.2 mmoles) potassium thioacetate(0.713 grams, 6.24 mmoles),4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.301 grams, 0.52mmole), tris(dibenzylideneacetone)dipalladium(0) (0.275 grams, 0.3mmoles), and diisopropylethyl amine (1.34 grams, 10.4 mmoles) in 50 mLdioxane was stirred at 23° for 18 hours. The mixture was diluted with100 mL ethyl ether and filtered. The filtrate was washed with 0.1Nhydrochloric acid, water, and saturated sodium chloride. The organicphase was dried (magnesium sulfate) and concentrated under reducedpressure. The residue was subjected to low pressure columnchromatography over silica gel 230-400 mesh eluting with a gradient of10-15% ethyl acetate in hexane. R-Thioacetic acidS-[5-(tert-butoxycarbonylamino-methyl)-5,6,7,8-tetrahydro-naphthalen-2-yl]esterwas obtained as a white solid, 0.9 grams (52%), m.p. 68-69°, M⁺H=336,[α]_(D)=+32.5° (c=1, chloroform).

Step 2 R-(6-Mercapto-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl)-carbamicacid tert-butyl ester

To a solution of R-thioacetic acidS-[5-(tert-butoxycarbonylamino-methyl)-5,6,7,8-tetrahydro-naphthalen-2-yl]ester(0.84 grams, 2.5 mmoles) in 10 mL methanol was added 1.0 mL (4 mmole) 4M sodium hydroxide. The solution was immediately concentrated underreduced pressure and the residue was partitioned between 10 mL 1.0 Mhydrochloric acid and 50 mL ethyl ether. The organic phase was washedwith water, dried (magnesium sulfate) and concentrated under reducedpressure to provideR-(6-mercapto-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl)-carbamic acidtert-butyl ester as a crystalline solid, 0.7 gram (95%), m.p. 98-99°,M⁺=293, [α]_(D)=+27.6° (c=1, chloroform).

Step 3 (R)4-[5-(tert-Butoxycarbonylamino-methyl)-5,6,7,8-tetrahydro-naphthalen-2-ylsulfanyl]-6-fluoro-benzoimidazole-1-carboxylicacid tert-butyl ester

The 6-fluoro-4-iodo-benzoimidazole-1-carboxylic acid tert-butyl esterused in this step was prepared from 5-fluoro-3-iodo-benzene-1,2-diamineaccording to the procedure of Weber et al., WO 9400124. Briefly, amixture of 5-fluoro-3-iodo-benzene-1,2-diamine (1.3 grams, 5.16 mmoles)and 1.5 mL of 96% formic acid was stirred at 100° for 3 hours, thencooled, and 35 mL 5% sodium hydroxide was added. The mixture was cooledin an ice bath and the resulting solid was collected, washed with waterand dried in vacuo to provide 1.16 grams (86%)6-fluoro-4-iodo-1H-benzoimidazole, m.p. 210-211° C. A mixture of 1.0gram (3.8 mmoles) of this benzimidazole, di-tert-butyl dicarbonate (0.92grams, 4.2 mmole), and 5 mg dimethylaminopyridine in 15 mL dioxane wasstirred at 80° C. for 20 hours, then concentrated under reducedpressure. Purification of the residue by column chromatography oversilica gel 230-400 mesh eluting with 30% ethyl acetate in hexane gave6-fluoro-4-iodo-benzoimidazole-1-carboxylic acid tert-butyl ester as acrystalline solid, 1.38 grams (100%), m.p. 73-74° C.

A mixture of 6-fluoro-4-iodo-benzoimidazole-1-carboxylic acid tert-butylester (0.33 gram, 0.92 mmole), tris(dibenzylideneacetone)dipalladium(0)(0.047 gram, 0.05 mmole),4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.058 gram, 0.1 mmole),diisopropylethyl amine (0.32 mL (1.84 mmole), andR-(6-mercapto-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl)-carbamic acidtert-butyl ester (0.3 gram, 1.02 mmole) in 6 mL dioxane was stirred at50° C. for 1.5 hours. The mixture was diluted with 30 mL ethyl ether andwashed with 2.5% hydrochloric acid, water, and 0.75M sodium carbonate.The organic phase was dried (magnesium sulfate) and concentrated underreduced pressure. The residue was subjected to column chromatography,first over silica gel 230-400 mesh eluting with a gradient of 5-40%ethyl acetate in hexane, and then over Activity I, neutral aluminaeluting with 50% ethyl acetate in hexane.(R)-4-[5-(tert-Butoxycarbonylamino-methyl)-5,6,7,8-tetrahydro-naphthalen-2-ylsulfanyl]-6-fluoro-benzoimidazole-1-carboxylicacid tert-butyl ester was obtained as an oil, 0.32 gram (66%). NMR(CDCl₃) ppm δ: 8.39 (s, 1H), 7.46 (dd, 1H, J=6.3 Hz, J=8.7 Hz), 7.29 (m,3H), 6.61 (dd, 1H, J=2.4 Hz, J=10 Hz), 4.67 (m, 1H), 3.44 (m, 1H), 3.32(m, 1H), 3.0 (m, 1H), 2.76 (m, 2H), 1.81 (m, 4H), 1.70 (s, 9H), 1.60 (s,9H).

Step 4(R)—C-[6-(6-Fluoro-1H-benzoimidazol-4-ylsulfanyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-methylamine

(R)-4-[5-(tert-Butoxycarbonylamino-methyl)-5,6,7,8-tetrahydro-naphthalen-2-ylsulfanyl]-6-fluoro-benzoimidazole-1-carboxylicacid tert-butyl ester was treated with metachloroperbenzoic acid usingthe procedure of step 8 of Example 15. The resulting4-[5-(tert-Butoxycarbonylamino-methyl)-5,6,7,8-tetrahydro-naphthalene-2-sulfonyl]-6-fluoro-benzoimidazole-1-carboxylicacid tert-butyl ester was deprotected following the procedure of step 10of Example 15 to giveC-[6-(6-Fluoro-1H-benzoimidazol-4-ylsulfanyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-methylamine,M+H=360.

Example 20(R)—N-[6-(2-Fluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-N′-cyano-guanidine

(R)—N-[6-(2-Fluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-N′-cyano-guanidinewas prepared by treatingC-[6-(2-Fluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-methylaminewith diphenylcyanoimidate according to the procedure reported in J. Med.Chem. 47, 12, 3201 (2004).

Example 21(R)-1-[6-(3-Fluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-3-methyl-urea

(R)-1-[6-(3-Fluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-3-methyl-ureawas prepared by treatment ofC-[6-(3-Fluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]methylaminewith methyl isocyanate according to the procedure of Najer et al.; Bull.Soc. Chim. Fr.; 1069-1071 (1957).

Example 22N-[2-(6-Benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-acetyl]-guanidine

The synthetic procedure described in this Example was carried outaccording to the process shown in Scheme Y.

(6-Benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-acetic acid (0.30grams, 0.80 mmole) and carbonyl diimidazole (0.13 gms, 0.90 mmole) in 30mL DMF was stirred for three hours at room temperature. Guanidinesulfate (90 mg) was added, followed by 0.1 ml diisopropylethylamine, andthe reaction mixture was stirred overnight. The reaction mixture wasdiluted with water, and the resulting white crystals were collected byfiltration, washed with water, and dried under vacuum to afford 190 mgofN-[2-(6-Benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-acetyl]-guanidine,M+H=372.

Similarly prepared from[6-(3-Fluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-aceticacid was(R)—N-{2-[6-(3-Fluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-acetyl}-guanidine,M+H=390.

Example 23N-[6-(3-Fluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-2-methylamino-acetamide

The synthetic procedure described in this Example was carried outaccording to the process shown in Scheme Z.

Step 1({[6-(3-Fluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-carbamoyl}-methyl)-methyl-carbamicacid benzyl ester

C-[6-(3-Fluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-methylaminehydrochloride (0.2 gms, 0.56 mmole),(Benzyloxycarbonyl-methyl-amino)-acetic acid (0.15 gms, 0.67 mmole),1-hydroxybenzotriazole (0.11 gms, 0.84 mmole), 0.16 gmsN-(3-dimethylaminopropyl)-N-ethylcarbodiimide (0.16 gms, 0.84 mmole) andtriethylamine (0.50 ml, 3.36 mmole) in 30 mL methylene chloride wasstirred at room temperature for 24 hours. The reaction was quenched with0.2 ml water, and the entire mixture was absorbed on to silica gel andmedium pressure chromatography, eluting with ethyl acetate, gave 0.15gms of({[6-(3-Fluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-carbamoyl}-methyl)-methyl-carbamicacid benzyl ester as an oil.

Step 2N-[6-(3-Fluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-2-methylamino-acetamide

To a stirring solution of({[6-(3-Fluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-carbamoyl}-methyl)-methyl-carbamicacid benzyl ester (0.15 g) in 20 ml methanol and 2 ml formic acid atroom temperature was added 0.1 gms of 10% palladium on carbon. Afterstirring for three hours the mixture was filtered thru Celite and theclear filtrate was concentrated to dryness. The residue wasrecrystallized from ethyl acetate and diethyl ether to give 0.090 gms ofN-[6-(3-Fluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-2-methylamino-acetamideformate salt: M+H=391.

Example 242-{[6-(3-Fluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]amino}-N-methyl-acetamide

The synthetic procedure described in this Example was carried outaccording to the process shown in Scheme AA.

Step 1{[6-(3-Fluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-amino}-aceticacid ethyl ester

C-[6-(3-Fluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-methylaminehydrochloride (0.5 gms, 1.41 mmole) and triethyl amine (0.2 ml, 1.55mmole) in 25 ml dichloroethane were stirred together for three minutes,and then the solution cooled in an ice-bath. A 50% solution ofethylgloxylate (0.32 ml, 1.55 mmole) in toluene was added, and thenfollowed by sodiumtriacetoxyborohydride (0.7 gms, 3.08 mmle). Thereaction was stirred for four hours and then was quenched by addition of2% sodium carbonate solution. The mixture was extracted twice with ethylacetate, and the combine organic extracts were washed with saturatedNaCl solution, dried over magnesium sulfate, filtered, and stripped toan oil under reduced pressure to give{[6-(3-Fluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-amino}-aceticacid ethyl ester. The HCl salt was crystallized from diethylether-methanol. Yield: 0.42 gms, M+H=406.

Step 22-{[6-(3-Fluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-amino}-N-methyl-acetamide

{[6-(3-Fluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-amino}-aceticacid ethyl ester (0.42 g) was dissolved in 20 m of 1.1 molar methylaminin methanol. The solution was stirred at room temperature for 24 hoursand then concentrated to an oil under reduced pressure. The oil wasdissolved in ethanol and 1N HCl in diethyl ether was added toprecipitate2-{[6-(3-Fluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-amino}-N-methyl-acetamideas a hydrochloride salt. Yield 0.045 gms, M+H=391.

Example 25(R)-[6-(3-Fluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-urea

The synthetic procedure described in this Example was carried outaccording to the process shown in Scheme BB.

C-[6-(3-Fluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-methylaminehydrochloride (0.5 gms, 1.41 mmole) and potassium cyanate (0.137 g, 1.69mmol) added to to 30 mL stirring water, and the mixture was heated to60° C. for five minutes. The reaction mixture was then cooled to roomtemperature, and the resulting white precipitate was collected byfiltration, washed with cold water, and dried under vacuum to give 0.408g of(R)-[6-(3-Fluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-urea,M+H=363.

Example 26(R)—N-[6-(3-Fluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-methanesulfonamide

The synthetic procedure described in this Example was carried outaccording to the process shown in Scheme CC.

C-[6-(3-Fluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-methylaminehydrochloride (0.5 gms, 1.41 mmole) was dissolved in 20 mL methylenechloride and 0.5 mL pyridine, and the mixture was cooled in an ice bath.Methanesulfonyl chloride (0.16 g, 1.41 mmol) was added dropwise, and thereaction mixture was stirred for five minutes at ice bath temperature,then allowed to warm to room temperature. The reaction mixture wasquenched by addition of water, and was extracted with methylenechloride. The organic layer was washed with water, dried (MgSO₄),filtered and concentrated under reduced pressure. The residue wasrecrystallized from diethyl ether to give 0.39 g of(R)—N-[6-(3-Fluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-methanesulfonamide,M+H=398.

Example 27 Formulations

Pharmaceutical preparations for delivery by various routes areformulated as shown in the following Tables. “Active ingredient” or“Active compound” as used in the Tables means one or more of theCompounds of Formula I.

Composition for Oral Administration Ingredient % wt./wt. Activeingredient 20.0% Lactose 79.5% Magnesium stearate  0.5%

The ingredients are mixed and dispensed into capsules containing about100 mg each; one capsule would approximate a total daily dosage.

Composition for Oral Administration Ingredient % wt./wt. Activeingredient 20.0% Magnesium stearate  0.5% Crosscarmellose sodium  2.0%Lactose 76.5% PVP (polyvinylpyrrolidine)  1.0%

The ingredients are combined and granulated using a solvent such asmethanol. The formulation is then dried and formed into tablets(containing about 20 mg of active compound) with an appropriate tabletmachine.

Composition for Oral Administration Ingredient Amount Active compound1.0 g Fumaric acid 0.5 g Sodium chloride 2.0 g Methyl paraben 0.15 gPropyl paraben 0.05 g Granulated sugar 25.5 g Sorbitol (70% solution)12.85 g Veegum K (Vanderbilt Co.) 1.0 g Flavoring 0.035 ml Colorings 0.5mg Distilled water q.s. to 100 ml

The ingredients are mixed to form a suspension for oral administration.

Parenteral Formulation Ingredient % wt./wt. Active ingredient 0.25 gSodium Chloride qs to make isotonic Water for injection 100 ml

The active ingredient is dissolved in a portion of the water forinjection. A sufficient quantity of sodium chloride is then added withstirring to make the solution isotonic. The solution is made up toweight with the remainder of the water for injection, filtered through a0.2 micron membrane filter and packaged under sterile conditions.

Suppository Formulation Ingredient % wt./wt. Active ingredient  1.0%Polyethylene glycol 1000 74.5% Polyethylene glycol 4000 24.5%

The ingredients are melted together and mixed on a steam bath, andpoured into molds containing 2.5 g total weight.

Topical Formulation Ingredients grams Active compound 0.2-2 Span 60 2Tween 60 2 Mineral oil 5 Petrolatum 10 Methyl paraben 0.15 Propylparaben 0.05 BHA (butylated hydroxy anisole) 0.01 Water q.s. 100

All of the ingredients, except water, are combined and heated to about60° C. with stirring. A sufficient quantity of water at about 60° C. isthen added with vigorous stirring to emulsify the ingredients, and waterthen added q.s. about 100 g.

Nasal Spray Formulations

Several aqueous suspensions containing from about 0.025-0.5 percentactive compound are prepared as nasal spray formulations. Theformulations optionally contain inactive ingredients such as, forexample, microcrystalline cellulose, sodium carboxymethylcellulose,dextrose, and the like. Hydrochloric acid may be added to adjust pH. Thenasal spray formulations may be delivered via a nasal spray metered pumptypically delivering about 50-100 microliters of formulation peractuation. A typical dosing schedule is 2-4 sprays every 4-12 hours.

Example 28 Radioligand Binding Studies

This example illustrates in vitro radioligand binding studies ofcompound of formula I.

The binding activity of compounds of this invention in vitro wasdetermined as follows. Duplicate determinations of 5-HT₆ ligand affinitywere made by competing for binding of [³H]LSD in cell membranes derivedfrom HEK293 cells stably expressing recombinant human 5-HT₆ receptor.Duplicate determinations of 5-HT_(2A) ligand affinity were made bycompeting for binding of [³H]Ketanserin(3-(2-(4-(4-fluorobenzoyl)piperidinol)ethyl)-2,4(1H,3H)-quinazolinedione)in cell membranes derived from CHO-K1 cells stably expressingrecombinant human 5-HT_(2A) receptor. Membranes were prepared from HEK293 cell lines by the method described by Monsma et al., MolecularPharmacology, Vol. 43 pp. 320-327 (1993), and from CHO-K1 cell lines asdescribed by Bonhaus et al., Br J Pharmacol. June; 115(4):622-8 (1995).

For estimation of affinity at the 5-HT₆ receptor, all determinationswere made in assay buffer containing 50 mM Tris-HCl, 10 mM MgSO₄, 0.5 mMEDTA, 1 mM ascorbic acid, pH 7.4 at 37° C., in a 250 microliter reactionvolume. For estimation of affinity at the 5-HT_(2A) receptor alldeterminations were made in assay buffer containing 50 mM Tris-HCl, 5 mMascorbic acid, 4 mM CaCl2, pH 7.4 at 32° C., in a 250 microliterreaction volume.

Assay tubes containing [³H] LSD or [³H]Ketanserin (5 nM), competingligand, and membrane were incubated in a shaking water bath for 75 min.at 37° C. (for 5-HT₆) or 60 min. at 32° C. (for 5-HT_(2A)), filteredonto Packard GF-B plates (pre-soaked with 0.3% PEI) using a Packard 96well cell harvester and washed 3 times in ice cold 50 mM Tris-HCl. Bound[³H] LSD or [³H] Ketanserin were determined as radioactive counts perminute using Packard TopCount.

Displacement of [³H]LSD or [³H]Ketanserin from the binding sites wasquantified by fitting concentration-binding data to a 4-parameterlogistic equation:

${binding} = {{basal} + \left( \frac{{B\; \max} - {basal}}{1 + 10^{- {{Hill}({{\log {\lbrack{ligand}\rbrack}} - {\log \; {IC}_{50}}}}}} \right)}$

where Hill is the Hill slope, [ligand] is the concentration of competingradioligand and IC₅₀ is the concentration of radioligand producinghalf-maximal specific binding of radioligand. The specific bindingwindow is the difference between the Bmax and the basal parameters.

Using the procedures of this Example, compounds of Formula I were testedand found to be selective 5-HT₆ antagonists, selective 5-HT_(2A)antagonists, or both. For example, the compound3-(6-Benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-propionamidineexhibited a pKi of approximately 9.85 for 5-HT₆, andN-(6-Benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl)-acetamidineshowed a pKi of approximately 9.55 for 5-HT_(2A).

Example 29 Cognition Enhancement

The cognition-enhancing properties of compounds of the invention may bein a model of animal cognition: the object recognition task model.4-month-old male Wistar rats (Charles River, The Netherlands) were used.Compounds were prepared daily and dissolved in physiological saline andtested at three doses. Administration was always given i.p. (injectionvolume 1 ml/kg) 60 minutes before T1. Scopolamine hydrobromide wasinjected 30 minutes after compound injection. Two equal testing groupswere made of 24 rats and were tested by two experimenters. The testingorder of doses was determined randomly. The experiments were performedusing a double blind protocol. All rats were treated once with each dosecondition. The object recognition test was performed as described byEnnaceur, A., Delacour, J., 1988, A new one-trial test forneurobiological studies of memory in rats. 1: Behavioral data. Behav.Brain Res. 31, 47-59.

While the present invention has been described with reference to thespecific embodiments thereof, it should be understood by those skilledin the art that various changes may be made and equivalents may besubstituted without departing from the true spirit and scope of theinvention. In addition, many modifications may be made to adapt aparticular situation, material, composition of matter, process, processstep or steps, to the objective spirit and scope of the presentinvention. All such modifications are intended to be within the scope ofthe claims appended hereto.

1-65. (canceled)
 66. The compound(R)-[6-(3-fluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-urea,or a pharmaceutically acceptable salt thereof.
 67. The compound(R)—N-(6-benzenesulfonyl-8-fluoro-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl)-acetamide,or a pharmaceutically acceptable salt thereof.
 68. A method of enhancingcognitive memory, the method comprising administering an effectiveamount of the compound of claim 65 to a subject in need thereof.
 69. Amethod of enhancing cognitive memory, the method comprisingadministering an effective amount of the compound of claim 66 to asubject in need thereof.
 70. A method of treating Alzheimer's disease,the method comprising administering an effective amount of the compoundof claim 65 to a subject in need thereof.
 71. A method of treatingAlzheimer's disease, the method comprising administering an effectiveamount of the compound of claim 66 to a subject in need thereof.